Bis(acridinecarboxamide) and bis(phenazinecarboxamide) as antitumor agents

ABSTRACT

A compound which is a bis(acridinecarboxamide) or bis(phenazinecarboxamide) derivative of formula (I): ##STR1## wherein each X, which may be the same or different in a given molecule, is --CH═ or --N═ each of R 1  to R 4  which may be the same or different, H, C 1  -C 4  alkyl, OH, SH, NH 2 , C 1  -C 4  alkoxy, aryloxy, NHR, N(R) 2 , SR, SO 2  R wherein R is C 1  -C 4  alkyl, CF 3 , NO 2  or halogen, or R 1  and R 2  together form a methylenedioxy group; each of R 5  and R 6 , which may be the same or different, is H or C 1  -C 4  alkyl; Z is (CH 2 ) n , (CH 2 ) n  O(CH 2 ) n , (CH 2 ) n  N(R 7 )(CH 2 ) n , (CH 2 ) n  N(R 7 )(CH 2 ) m  N(R 7 )(CH 2 ) n  or (CH 2 ) n  N(CH 2  CH 2 ) 2  N(CH 2 ) n  wherein R 7  is H or C 1  -C 4  alkyl and n and m, which may be the same or different, are each an integer of 1 to 4; or a pharmaceutically acceptable acid addition salt or N-oxide thereof; has activity as an antitumor and antibacterial agent.

This application is a 371 of PCT/GB97/0286, filed Oct. 17, 1997.

The present invention relates to compounds useful as antitumor agents, to their production and to pharmaceutical compositions containing them.

Many compounds which bind reversibly to DNA by intercalation are known to have cellular antiproliferative properties and in vivo antitumor effects, mediated principally through their inhibition of topoisomerase enzymes. For example, the acridine derivatives amsacrine [Issell, Cancer Treat. Rev. 1980, 7, 73], asulacrine [Harvey et al., Eur. J. Cancer, 1991, 27, 1617] and acridinecarboxamide [Finlay et al., Eur. J. Cancer 1996, 32A, 708] are clinical anticancer drugs or in clinical trial, and related 9-azaacridines (phenazines) have been reported to have in vivo antitumor properties in animal models [Rewcastle et al., J. Med. Chem., 1987, 30, 843].

It has now been found that a series of bis(acridinecarboxamide) and bis(9-phenazinecarboxamide) derivatives have antitumor properties. The present invention therefore provides a compound which is a bis(acridinecarboxamide) or bis(phenazinecarboxamide) derivative of formula (I): ##STR2## wherein each X, which may be the same or different in a given molecule, is --CH═ or --N═; each of R₁ to R₄ which may be the same or different, is H, C₁ -C₄ alkyl , OH, SH, NH₂, C₁ -C₄ alkoxy, aryl, aryloxy, NHR, N(R)₂, SR or SO₂ R wherein R is C₁ -C₄ alkyl, CF₃, NO₂ or halogen, or R₁ and R₂ form together with the carbon atoms to which they are attached, a methylenedioxy group; each of R₅ and R₆, which may be the same or different, is H or C₁ -C₄ alkyl; Z is (CH₂)_(n), (CH₂)_(n) O(CH₂)_(n), (CH₂)_(n) N(R₇)(CH₂)_(n), (CH₂)_(n) N(R₇)(CH₂)_(m) N(R₇)(CH₂)_(n) or (CH₂)_(n) N(CH₂ CH₂)₂ N(CH₂)_(n), (CH₂)_(n) CONH(CH₂)_(m) or (CH₂)_(n) CONH(CH₂)_(m) NHCO(CH₂)_(n) wherein R₇ is H or C₁ -C₄ alkyl and n and m, which may be the same or different, are each an integer of 1 to 4; or a pharmaceutically acceptable acid addition salt or N-oxide thereof; with the exception of compounds wherein each X is N, each of R₁ to R₆ is H, the carboxamide moiety is attached to position 1 of each phenazine ring and Z is (CH₂)₂ NH(CH₂)₂, (CH₂)₃ NH(CH₂)₃, (CH₂)₃ N(CH₂ CH₂)₂ N(CH₂)₃, (CH₂)₂ NH(CH₂)₂ NH(CH₂)₂ or (CH₂)₃ NH(CH₂)₂ NH(CH₂)₃.

In formula (I) the ring numbering in each tricylic chromophore differs depending on whether X is --CH═ (acridine derivatives) or --N═ (phenazine derivatives). The numbering used in each case, with reference to one tricyclic moiety, is as follows: ##STR3##

In formula (I) the substituents R₁ and R₂, and R₃ and R₄, may occupy any one of the available ring positions in their respective tricyclic chromophores. Thus when X in a tricyclic moiety is --CH═ then R₁ and R₂, or R₃ and R₄ if appropriate, may each be bonded to any one of the available ring positions 1 to 8 not occupied by the carboxamide moiety --C(O)--N(R₅)--. The carboxamide moiety in turn may be bonded to any one of ring positions 1, 2, 3 and 4, preferably 1 or 4. Typically when X in a given tricyclic chromophore is --CH═ one of R₁ and R₂, or R₃ and R₄ if appropriate, is hydrogen and the other is hydrogen or is a substituent as defined above for formula (I) bonded at any one of ring positions 1 to 8, and the carboxamide moiety is bonded at position 1 or 4.

When X in a tricyclic moiety is --N═ then R₁ and R₂, or R₃ and R₄ if appropriate, may each be bonded to any one of the available ring positions 1 to 4 and 6 to 9 which are not occupied by the carboxamide moiety, in particular one of positions 6 to 9. The carboxamide moiety, in turn, may be bonded to either of the ring positions 1 and 2, preferably 1. Typically, when X in a given tricyclic chromophore is --N═ one of R₁ and R₂, or R₃ and R₄ if appropriate, is hydrogen and the other is hydrogen or is a substituent as defined above for formula (I) at any one of ring positions 1 to 4 or 6 to 9, especially 6, 7, 8 or 9, and the carboxamide moiety is bonded at position 1 or 4.

When the left- and right-hand tricyclic chromophores in formula (I) are identical the compounds are structurally symmetric. When the two chromophores differ in the definition of one or more substituents the compounds are structurally asymmetric. In a preferred aspect of the invention the compounds are structurally symmetric.

A C₁ -C₄ alkyl group may be linear or branched, for instance methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl. A C₁ -C₄ alkoxy group may similarly be linear or branched, for instance methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy or t-butoxy. A halogen is, for example, fluorine, chlorine, bromine or iodine.

In one aspect of the invention the compound is a bis(acridine carboxamide)derivative of the formula (Ia): ##STR4## wherein each of R₁ and R₃, which are the same or different, is C₁ -C₄ alkoxy, C₁ -C₄ alkyl or halogen, each of R₁ and R₄, which are the same or different, is hydrogen, C₁ -C₄ alkoxy, C₁ -C₄ alkyl or halogen and each of R₅ and R₆ is H; or a pharmaceutically acceptable salt or N-oxide thereof.

In another aspect of the invention the compound is a bis(phenazinecarboxamide) derivative of formula (Ib): ##STR5## wherein each of R₁ and R₃, which are the same or different, is C₁ -C₄ alkoxy, C₁ -C₄ alkyl or halogen, each of R₂ and R₄, which are the same or different, is hydrogen, C₁ -C₄ alkoxy, C₁ -C₄ alkyl or halogen and each of R₅ and R₆ is H; or a pharmaceutically acceptable salt or N-oxide thereof.

Examples of specific compounds of the invention are depicted in the following Table 1 by means of their substitution patterns. The compounds are all symmetric, which is to say that the left hand tricyclic chromophore is identical to the right hand one. Thus, R₁ ═R₃ and R₂ ═R₄ in formula (I).

                  TABLE 1                                                          ______________________________________                                         No.   R.sub.1═R.sub.3                                                                    R.sub.2 ═R.sub.4                                                                    X     Z                                                 ______________________________________                                          1    1-Me    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3               2    1-Cl    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3               3    2-Me    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3               4    2-Cl    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3               5    3-Me    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3               6    5-Me    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3               7    5-Et    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3               8    5-iPr   H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3               9    5-Ph    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              10    5-OMe   H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              11    5-F     H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              12    5-Cl    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              13    5-Br    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              14    5-CF.sub.3                                                                             H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              15    6-OMe   H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              16    6-F     H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              17    6-Cl    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              18    6-Br    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              19    6-CF.sub.3                                                                             H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              20    6-NMe.sub.2                                                                            H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              21    7-Me    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              22    7-Et    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              23    7-iPr   H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              24    7-tBu   H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              25    7-Ph    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              26    7-OMe   H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              27    7-F     H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              28    7-Cl    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              29    7-Br    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              30    8-Me    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              31    8-Cl    H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              32    5-Me    7-Me     --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              33    H       H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              34    H       H        --CH═                                                                            (CH.sub.2).sub.2 NH(CH.sub.2).sub.2               35    H       H        --CH═                                                                            (CH.sub.2).sub.3 NH(CH.sub.2).sub.3               36    H       H        --CH═                                                                            (CH.sub.2).sub.3 NpipN(CH.sub.2).sub.3            37.sup.#                                                                             H       H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              38    H       H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              39.sup.#                                                                             H       H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              40    6-Me    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              41    6-Cl    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              42    7-Me    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              43    7-OMe            --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              44    7-Cl    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              45    8-Me    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              46    8-OMe   H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              47    9-Me    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              48    9-Me    H        --N═                                                                             (CH.sub.2).sub.3 NpipN(CH.sub.2).sub.3            49    9-Me    H        --N═                                                                             (CH.sub.2).sub.2 NH(CH.sub.2).sub.2 NH(CH.sub                                  .2).sub.2                                         50    9-OMe   H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              51    9-OPh   H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              52    9-F     H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              53    9-Cl    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              54    9-NMe.sub.2                                                                            H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              55    5-NMe.sub.2                                                                            H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              56    7-NMe.sub.2                                                                            H        --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              57    5-Me    8-Me     --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              56    1-Me    5-Me     --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              59    8-Cl    5-Me     --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              60    1-Cl    5-Me     --CH═                                                                            (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              61    3-Me    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              62    3-Cl    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              63    2-Cl    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              64    8-Cl    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              65    6-Me    9-Me     --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              66    6-Cl    9-Me     --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              67    4-Me    H        --N═                                                                             (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3              68    9-Me    H        --N═                                                                             (CH.sub.2).sub.3 NH(CH.sub.2).sub.2 NH(CH.sub                                  .2).sub.3                                         69    6-Me    9-Me     --N═                                                                             (CH.sub.2).sub.2 NH(CH.sub.2).sub.2 NH(CH.sub                                  .2).sub.2                                         70    9-Me    H        --N═                                                                             (CH.sub.2).sub.3 NH(CH.sub.2).sub.4 NH(CH.sub                                  .2).sub.3                                         71    5-Me    H        --CH═                                                                            (CH.sub.2).sub.2 NH(CH.sub.2).sub.2 NH(CH.sub                                  .2).sub.2                                         72    H       H        --CH═                                                                            (CH.sub.2).sub.2 NH(CH.sub.2).sub.2 NH(CH.sub                                  .2).sub.2                                         73    9-Me    H        --N═                                                                             (CH.sub.2).sub.2 NH(CH.sub.2).sub.3 NH(CH.sub                                  .2).sub.2                                         74    6-Cl    9-Me     --N═                                                                             (CH.sub.2).sub.2 NH(CH.sub.2).sub.2 NH(CH.sub                                  .2).sub.2                                         74a   9-Me    H        --N═                                                                             (CH.sub.2).sub.2 NMe(CH.sub.2).sub.2                                           NMe(CH.sub.2).sub.2                               ______________________________________                                    

    ______________________________________                                         No.  chromophore Z            chromophore                                      ______________________________________                                         75   acridine-4- (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3                                                        phenazine-1-                                          carboxamide              carboxamide                                      76   5-methylacridine-                                                                          (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3                                                        9-methylphenazine-                                    4-carboxamide            1-carboxamide                                    77   phenazine-1-                                                                               (CH.sub.2).sub.3 NMe(CH.sub.2).sub.3                                                        9-methylphenazine-1-                                  carboxamide              carboxamide                                      78   5-methylacridine-                                                                          (CH.sub.2)NH(CH.sub.2).sub.2 --                                                             9-methylphenazine-1-                                  4-carboxamide                                                                              NH(CH.sub.2).sub.2                                                                          carboxamide                                      79   acridine-4- (CH.sub.2).sub.2 NH(CH.sub.2).sub.2 --                                                      phenazine-1-carboxamide                               carboxamide NH(CH.sub.2).sub.2                                            ______________________________________                                    

# denotes carboxamide at 2-position of acridine or phenazine. In all other cases the carboxamide is at the 4-position in acridines (X is --CH═) and the 1-position in phenazines (X is --N═).

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts and N-oxides are produced by a process which comprises reacting two moles of an acridinecarboxylic acid or 9-azaacridinecarboxylic acid (phenazinecarboxylic acid) derivative of the formula (II): ##STR6## wherein R₁, R₂ and X are defined as above and A is OH, Cl, or N-imidazolyl, with one mole of a bis(amine) of formula (III):

    NHR.sub.5 --Z--NHR.sub.6                                   (III)

wherein R₅, R₆ and Z are as defined as above, and, if desired, converting the resulting compound into a pharmaceutically acceptable acid addition salt or N-oxide thereof. This coupling reaction is typically performed in a non-hydroxylic solvent, preferably THF. The reaction is conveniently performed at a temperatures of from -10° C. to 50° C.

The derivatives of formula (I) may be converted into pharmaceutically acceptable acid addition salts, and salts may be converted into the free compound, by conventional methods. For instance, the acid addition salts may be prepared by contacting the free base with an appropriate amount of the desired acid in a conventional manner. Suitable salts include salts with both organic and inorganic acids. Examples of suitable acids are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, methanesulfonic and the like. Depending on structure, and on the conditions, the compounds may form multicationic forms.

The optional conversion of a compound of formula (I) into another compound of formula (I) may be carried out by conventional methods. For instance, a fluoro group in a compound of formula may be substitued by an amino or thiol group to give an amine or thioether, respectively; a phenol or thiol group in a compound of formula (I) may be alkylated to give an ether or thioether, respectively; an amino group may be acylated to give an N-acetate; and a nitro group may be reduced to give an amine. These are all routine conversions in organic chemistry.

Compounds of formula (I) may be converted into the corresponding N-oxide by conventional techniques, for instance by dissolving them in CH₂ Cl₂ and treating with 2-(phenylsulphonyl)-3-phenyloxaridine for 15 mins to 24 hours, preferably for 1 hour, at a temperature of from 0° to 60°, preferably 20° C. The free base forms can be regenerated by treating the salt form with a base. The free base forms differ from their respective salt forms in certain physical properties, but are otherwise equivalent to the respective free base forms for the purposes of the invention.

The bis(amines) of general formula (III) are known compounds, and are commercially available or preparable by methods described in the literature. Specific examples of such compounds include NH₂ (CH₂)₆ NH₂, NH₂ (CH₂)₃ O(CH₂)₃ NH₂, NH₂ (CH₂)₃ NH(CH₂)₃ NH₂, NH₂ (CH₂)₃ NMe(CH₂)₃ NH₂, NH₂ (CH₂)₂ NH(CH₂)₂ NH(CH₂)₂ NH₂ and NH₂ (CH₂)₃ N(CH₂ CH₂)₂ N(CH₂)₃ NH₂.

The substituted acridine acids of formula II wherein X is CH and A is OH can be prepared by a process described in Atwell et al., J. Med. Chem., 1984, 27, 1481. This involves Al/Hg reduction of the corresponding acridone-4-carboxylic acids of formula IV followed by re-oxidation with FeCl₃ or other suitable mild oxidant as depicted in scheme 1 below. ##STR7##

The acridone-4-carboxylic acids of formula IV can in turn be prepared by a variety of known methods, including Jourdan-Ullman coupling of substituted anthranilic acids and haloacids as described in Denny et al., J. Med. Chem. , 1987, 30, 658, Jourdan-Ullman coupling of iodoisophthalic acid with substituted anilines as described in Rewcastle and Denny, Synthesis, 1985, 217 or reaction of substituted diphenyliodonium carboxylates with substituted anilines as described in Rewcastle and Denny, Synthesis, 1985, 220, followed by cyclization of the diphenylamine diacids and diphenylamine monoesters so formed with PPA or PPE to give the acridones. Reaction of the acridine-4-carboxylic acids of formula II wherein A is OH with 1.1 equivalents of 1,1'-carbonyldiimidazole in DMF at 10-40° C. for 10 min to 24 h gives the corresponding imidazolide derivatives of compounds of formula II. These can be isolated by filtration and reacted with 0.5 equivalents of a bisamine of formula III to give the required compounds of formula I.

Some of the substituted acridine-4-carboxylic acids of formula (II) and derivatives thereof, useful as intermediates in the preparation of compounds of general formula (I), are novel. Accordingly, the invention further provides a compound of formula (IIa): ##STR8## wherein X, R₁ and R₂ are as defined for formula (I) and A is OH, Cl, N-imidazolyl or OR wherein R is branched or unbranched, saturated or unsaturated C₁ -C₆ alkyl, or aryl, with the exception of compounds wherein:

(i) X is CH, A is OH, one of R₁ and R₂ is H and the other is H, Cl, OMe or Me and the --COA moiety is at the 4-position of the tricyclic chromophore; and

(ii) X is N, A is OH, one of R₁ and R₂ is H and the other is H, Cl, OMe or Me and the COA moiety is at the 1-position of the tricyclic chromophore.

These novel compounds of formula (IIa) can be prepared by the process which is depicted fully in Scheme 2 below. Accordingly, the invention further provides a process for producing a compound of formula (IIa), which process comprises cyclizing a compound of formula (X): ##STR9## wherein R₁ and R₂ are as defined above. The cyclization is typically carried out under acid conditions, for example using neat trifluoroacetic acid for a period of 12 hours, at a temperature of from 20° to 60° C.

The compounds of formula (X) are produced as indicated in scheme 2 below. ##STR10##

Throughout scheme 2, R₁ and R₂ are as defined above for general formula (I). The substituted diphenylamine acids (VII) are formed by coupling of substituted anthranilic acids (V) with methyl 2-halobenzoates (VI), typically the iodobenzoate and a copper catalyst in a polar solvent, typically butane-2,3-diol. This is described in Rewcastle and Denny, Synth. Comm., 1987, 17, 309. Reaction of the substituted diphenylamine acids with 1,1'-carbonyldiimidazole (CDI) in a polar solvent, typically THF, gives the imidazolides of formula (VIII), which are reduced in situ by excess of a metal-based reducing agent suitably sodium borohydride to the alcohols of formula (IX).

Oxidation of the alcohols with solid MnO₂ in a polar solvent, typically ethyl acetate or acetone, gives the corresponding aldehydes of formula (X), which are cyclized as indicated above to form substituted acridine esters, which are compounds of formula (II) wherein A is OMe. These esters can be hydrolyzed under acidic or basic conditions to the corresponding acids, which are compounds of formula (II) wherein A is OH. These in turn can be activated by reaction with 1,1'-carbonyldiimidazole in a polar solvent (preferably dry DMF) to give the corresponding imidazolide derivative, which are compounds of formula (IIa) wherein A is N-imidazolyl, or by treatment with thionyl chloride in an inert solvent, typically dichloroethane, to give the corresponding acid chlorides which are compounds of formula (II) wherein A is Cl.

These latter intermediates can be coupled with bis(amines) of formula (III) as described above, to give the desired compounds of general formula (I). Alternatively, the substituted acridine esters of formula(II wherein A═OMe can be reacted directly with bis(amines) of general formula III in a polar solvent, preferably ethanol or isopropanol, to give the compounds of general formula (I).

The phenazine acids, namely compounds of formula II wherein X is N and A is OH, can be prepared by methods reported in the literature. Examples include J. Med. Chem. 1987, 30, 843; Synth. Comm. 1987, 17, 1171; EP-A-172,744, and Chem. Abstr. 1986, 105, 97496p. These may then be converted to compounds of general formula I by the methods outlined above.

Further compounds of general formula (I) can also be made by the general method outlined in Scheme 3 which follows. In this approach, reaction of compounds of formula (II) (where A=imidazolide) with a mono-protected amine of formula (XI) gives an intermediate of formula (XII). Removal of the R₈ protecting group gives amines of formula (XIII), which can be coupled with a further equivalent of a compound of formula (II) (where A=imidazolide) to give compounds of formula (I). In Scheme 3, R₁ -R₅, Z and R₆ are as defined above for formula (I), with the exception that R₇ can also be BOC, trityl, CO₂ CF₃ or other suitable amine protecting group, and R₈ is defined as BOC, trityl, CO₂ CF₃ or other suitable amine protecting group. ##STR11##

The compounds of formula (I) and their salts and N-oxides have been found in biological tests to have anti-tumor activity. The results are set out in Example 78 which follows. The compounds have negligible toxicity and may therefore be used as anti-tumor agents. A human or animal patient harbouring a tumor may thus be treated by a method which comprises administering thereto a compound of formula (I) or a salt or N-oxide thereof. The condition of a patient suffering from cancer may thereby be improved. Examples of tumors which the compounds of formula (I) may be used to treat include lung and colon tumors, melanoma and central nervous system (CNS) tumors.

The present compounds can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously. The present compounds may therefore be given by injection or infusion.

The dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered alone to adult humans is 50 mg/m² to 5 g/m². Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, for instance 3 times daily, infusion over several hours, for instance 3 hours, and/or repeated administration.

The present compounds of formula (I) and their salts and N-oxides are formulated for use as a pharmaceutical or veterinary composition . The present invention therefore further provides a pharmaceutical or veterinarily composition which comprises a pharmaceutically or veterinarily acceptable carrier or diluent and, as an active ingredient, a compound of formula (I) or a salt or N-oxide thereof.. The compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form.

For example, the solid oral forms may contain, together with the active compound, diluents, such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures, dye-stuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates. Such preparations may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugar coating, or film-coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. In particular a syrup may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. In particular a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolize to glucose or which only metabolize a very small amount to glucose. The suspensions and the emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. Typically the compounds of formula (I) are formulated as aqueous solutions of hydrochloride or other pharmaceutically acceptable salts. Solutions for intravenous injection or infusion may contain a carrier, for example, sterile water which is generally Water for Injection.

The invention will be further described in the following Examples, with reference to the accompanying Figure, in which:

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 is a plot of tumor volume in mm³ (y axis) against time in days (x axis) for the growth delay of colon 38 tumor cells in in vivo testing in mice, as described in Example 80 which follows.

EXAMPLE 1 Preparation of Compound 22 of Table I by the Method of Scheme 1

A mixture of 2-iodoisophthalic acid (2.92 g, 10 mmol), 4-ethylaniline (1.82 g, 15 mmol), CuCl (1 g), 2,3-butanediol (12 mL) and benzene (10 mL) was heated and stirred with the benzene being allowed to distil off. When the internal temperature of the reaction mixture reached 100° C., N-ethylmorpholine (6 mL) was added, and the reaction mixture was stirred for an additional 4 hours at 120° C. The reaction mixture was then diluted with 0.5 M NH₄ OH (50 mL), treated with charcoal and filtered through Celite. Acidification with 2 M HCl afforded a precipitate which was extracted into EtOAc (2×100 mL), filtered through Celite and further extracted with 0.5M NH₃ (100 mL). Acidification with concentrated HCl and recrystallization of the isolated product gave 2-[(4-ethyl)phenylamino]isophthalic acid (2.36 g, 83%), mp (EtOAc/pet. ether) 194.0-195.4° C. ¹ H NMR [(CD₃)₂ SO] δ 1.15 (t, J=7.6, 3 H, CH₃), 2.51 (q, J=7.6 Hz, 2 H, CH₂), 6.84 (d, J=8.4 Hz, 2 H, H-2' and H-6' or H-3' and H-5'), 6.97 (t, J=7.7 Hz, 1 H, H-5), 7.04 (d, J=8.4 Hz, 2 H, H-3' and H-5' or H-2' and H-6'), 7.92 (d, J=7.6 Hz, 2 H, H-4 and H-6), 9.65 (br s, 1 H, NH) and 12.90 (br s, 2 H, 2×COOH). Anal. (C₁₆ H₁₄ NO₄) C, H, N.

Reaction of the above diacid (1.43 g, 5 mmol) with polyphosphoric acid (38 g) was achieved by heating the mixture at 120° C. for 2 h. The cooled mixture was poured into boiling water (250 mL), resulting in a suspension of yellow precipitate. The precipitate was removed by filtration and dissolved in a mixture of MeOH (100 mL) and 1M NaOH (100 mL) which was heated and then filtered whilst still hot. Acidification of this mixture using glacial acetic acid gave a yellow solid, which was recrystallized to give 7-ethyl-9-oxoacridan-4-carboxylic acid (1.14, g, 89%), mp (H₂ O) 301° C. (dec). ¹ H NMR [(CD₃)₂ SO] δ 1.26 (t, J=7.6 Hz, 3 H, CH₃), 2.74 (q, J=7.6 Hz, 2 H, CH₂), 7.33 (t, J=7.7 Hz, 1 H, H-2), 7.64 (dd, J=8.5, 2.1 Hz, 1 H, H-6), 7.71 (d, J=8.5 Hz, 1 H, H-5), 8.04 (br s, 1 H, H-8), 8.42 (dd, J=7.5, 1.7 Hz, 1 H, H-3), 8.52 (dd, J=8.0, 1.7 Hz, 1 H, H-1), 11.98 (s, 1 H, NH) and 13.85 (br s, 1 H, COOH). Anal. (C₁₆ H₁₃ NO₃) C, H, N.

A suspension of the above acridone acid (1.00 g, 3.75 mmol) in 50% aqueous EtOH was stirred and heated, then sufficient triethylamine added to obtain a clear yellow solution. Portions of aluminium foil (0.83 g) were amalgamated in a solution of HgCl₂ (3 g) in EtOH, then added to the above vigorously boiling solution over 30 min. After the reaction was observed to be complete by tlc, the reaction mixture was filtered and the solids collected were washed with a solution of KOH in aqueous EtOH. The filtrate was then strongly acidified with concentrated HCl and treated with FeCl₃ under reflux for 45 min. The reaction mixture was concentrated under reduced pressure and sufficient potassium acetate added until the pH was neutral. Crystallization of the product occurred upon cooling and filtration and recrystallisation of the resulting brown solid gave 7-ethylacridine-4-carboxylic acid (0.77 g, 82%), mp (acetone) 210-211.5° C. ¹ H NMR [(CD₃)₂ SO] δ 1.35 (t, J=7.5 Hz, 3 H, CH₃), 2.91 (q, J=7.5 Hz, 2 H, CH₂), 7.83 (dd, J=8.3, 7.2 Hz, 1 H, H-2), 7.97 (dd, J=9.0. 1.9 Hz, 1 H, H-6), 8.09 (br s, 1 H, H-8), 8.26 (d, J=9.0 Hz, 1 H, H-5), 8.54 (dd, J=8.4, 1.2 Hz, 1 H, H-1), 8.71 (br d, J=7.0 Hz, 1 H, H-3), 9.43 (s, 1 H, H-9), 17.09 (br s, 1 H, COOH). Anal. (C₁₆ H₁₃ NO₂) C, H, N.

The above acridine acid (0.30 g, 1.2 mmol) was reacted with CDI (0.38 g, 2.39 mmol) in dry DMF (50 mL) for 4 h at 50° C. The DMF was removed under reduced pressure, and the resulting oil was dissolved in a mixture of petroleum ether and CH₂ Cl₂ (20 mL, 3:1). Upon cooling, the imidazolide crystallized out and this crude material was used in the following coupling reaction. The coupling was carried out by dissolving 3,3'-diamino-N-methyldipropylamine (0.09 g) in THF (50 mL), cooling to 0° C. (ice/water), and adding the crude imidazolide portionwise. The reaction mixture was allowed to stir overnight at room temperature, the THF removed, and the residue diluted with CH₂ Cl₂ (100 mL) which was subsequently washed with 1M Na₂ CO₃ (50 mL). The CH₂ Cl₂ layer was dried with Na₂ SO₄, the solvent removed under reduced pressure, and the resulting brown oil purified by chromatography on alumina (0.5% MeOH in CH₂ Cl₂ as eluant) to give bis[(7-ethylacridine-4-carboxamido)-propyl]methylamine (22) (0.17 g, 47%) as a yellow oil. ¹ H NMR (CDCl₃) δ 1.28 (t, J=7.5 Hz, 6 H, 2×CH₃), 2.03-2.11 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.40 (s, 3 H, NCH₃), 2.70 (q, J=7.6 Hz, 4 H, 2×CH₂ CH₃), 2.79 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.74 (q, J=6.2 Hz, 4 H, 2×CH₂ NH), 7.46 (br s, 2 H, H-8), 7.48 (dd, J=8.9, 1.8 Hz, 2 H, H-6), 7.56 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 7.89 (d, J=8.8 Hz, 2 H, H-5), 7.98 (dd, J=8.3, 1.5 Hz, 2 H, H-1), 8.51 (s, 2 H, H-9), 8.86 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.80 (br t, J=5.0 Hz, 2 H, CONH). HRMS. (FAB⁺) m/z calcd for C₃₉ H₄₂ N₅ O₂ 612.3339 (MH⁺), found 612.3333.

EXAMPLE 2 Preparation of Compound 1 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 1-methylacridine-4-carboxylic acid gave bis[(1-methylacridine-4-carboxamido)propyl]methylamine (1) as a yellow oil (91%). ¹ H NMR (CDCl₃) δ 2.02-2.09 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.75 (t, J=7.5 Hz, 4 H, 2×CH₂ NCH₃), 2.80 (d, J=0.7 Hz, 6 H, 2CH₃), 3.73 (q, J=6.1 Hz, 4 H, 2×CH₂ NH), 7.36 (ddd, J=8.2, 6.7, 0.9 Hz, 2 H, H-6 or H-7), 7.43 (dd, J=7.6, 0.8 Hz, 2 H, H-2), 7.66 (ddd, J=8.7, 6.7, 1.4 Hz, 2 H, H-7 or H-6), 7.80 (d, J=8.0 Hz, 2 H, H-5 or H-8), 7.99 (dd, J=8.7, 0.8 Hz, 2 H, H-8 or H-5), 8.78 (s, 2 H, H-9), 8.80 (d, J=7.3 Hz, 2 H, H-3) and 11.77 (br t, J=5.1 Hz, 2 H, 2NH). HRMS (FAB⁺) m/z calcd. for C₃₇ H₃₈ N₅ O₂ 584.3026 (MH⁺), found 584.3041. Anal. (C₃₇ H₃₇ N₅ O₂.0.5H₂ O) C, H, N.

EXAMPLE 3 Preparation of Compound 2 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 1-chloroacridine-4-carboxylic acid gave bis[(1-chloroacridine-4-carboxamido)propyl]methyl-amine (2) (83%), mp (CH₂ Cl₂ /n-hexane) 94-96° C. ¹ H NMR (CDCl₃) δ 2.02-2.09 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.39 (s, 3 H, NCH₃), 2.79 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.72 (q, J=6.1 Hz, 4 H, 2×CH₂ NH), 7.31 (ddd, J=8.2, 6.7, 0.8 Hz, 2 H, H-6 or H-7), 7.63 (ddd, J=8.7, 6.7, 1.3 Hz, 2 H, H-7 or H-6), 7.67 (d, J=7.9 Hz, 2 H, H-2), 7.74 (br d, J=8.0 Hz, 2 H, H-5 or H-8), 7.91 (br d, J=8.7 Hz, 2 H, H-8 or H-5), 8.75 (d, J=8.0 Hz, 2 H, H-3), 8.98 (s, 2 H, H-9), 11.45 (br t, J=4.8 Hz, 2 H, 2×CONH). HRMS(FAB⁺) m/z calcd. for C₃₅ H₃₂ ³⁵ Cl₂ N₅ O₂ 624.1933 (MH⁺), found 624.1935 Anal. (C₃₅ H₃₁ Cl₂ N₅ O₂) C, H, N.

EXAMPLE 4 Preparation of Compound 3 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 2-methylacridine-4-carboxylic acid gave bis[(2-methylacridine-4-carboxamido)propyl]methylamine (3) as a yellow oil (90%). ¹ H NMR (CDCl₃) δ 2.01-2.08 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.60 (s, 3 H, 2×CH₃), 2.73 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.70-3.77 (m, 4 H, 2CH₂ NH), 7.38 (br t, J=7.8 Hz, 2 H, H-6 or H-7) 7.64 (ddd, J=8.6, 6.9, 1.5 Hz, 2 H, H-7 or H-6), 7.76 (br s, 2 H, H-1), 7.79 (d, J=8.3 Hz, 2H, H-5 or H-8), 8.00 (d, J=8.2 Hz, 2 H, H-8 or H-5), 8.55 (s, 2 H, H-9), 8.76 (d, J=2.2 Hz, 2 H, H-3) and 11.79 (br t, J=5.0 Hz, 2 H, 2×CONH). HRMS(FAB⁺) m/z calcd. for C₃₇ H₃₈ N₅ O₂ 584.3026 (MH⁺), found 584.3031. Anal. (C₃₇ H₃₇ N₅ O₂) C, H,N.

EXAMPLE 5 Preparation of Compound 4 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al, J. Med Chem. 1987, 30, 664] 2-chloroacridine-4-carboxylic acid gave bis[2-chloroacridine-4-carboxamido)propyl]methylamine (4) as a yellow solid (54%), mp (CH₂ Cl₂ /n-hexane) 175.5-176.5° C. ¹ H NMR (CDCl₃) δ 2.00-2.07 (m, 4H,2×CH₂ CH₂ CH₂), 2.38 (s, 3H, NCH₃), 2.75 (t,J=7.4 Hz, 4H, 2×CH₂ NCH₃), 3.71 (q, J=6.2 Hz, 4H, 2×CH₂ NH), 7.42 (ddd, J=8.3, 6.6, 0.9 Hz, 2H, H-6 or H-7), 7.68 (ddd, J=8.7, 6.6, 1.3 Hz, 2H, H-7 or H-6), 7.74 (br d, J=7.9 Hz, 2H, H-5 or H-8), 7.93-7.96 (m, 4H, H-1 and H-8 or H-5), 8.49 (s, 2H, H-9), 8.74 (d, J=2.5 Hz, 2H, H-3) and 11.52 (br t, J=5.0 Hz, 2×NH). HRMS (FAB⁺) m/z calcd. for C₃₅ H₃₂ ³⁵ Cl₂ N₅ O₂ 624.1993 (MH⁺), found 624.1900. Anal (C₃₅ H₃₁ Cl₂ N₅ O₂) C,H,N.

EXAMPLE 6 Preparation of Compound 5 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 3-methylacridine-4-carboxylic acid, followed by purification on alumina followed by silica gel chromatography, gave bis[(3-methylacridine-4-carboxamido)propyl]methyl-amine (5) as a pale yellow gum (15%). ¹ H NMR (CDCl₃) δ 1.78-1.84 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.18 (s, 3 H, NCH₃), 2.48 (s, 6 H, 2×CH₃), 2.67 (t, J=6.5 Hz, 4 H, 2×CH₂ NCH₃), 3.56 (q, J=6.1 Hz, 4 H, 2×CH₂ NH), 7.19 (d, J=8.6 Hz, 2 H, H-1 or H-2), 7.33 (ddd, J=8.4, 6.6, 1.0 Hz, 2 H, H-6 or H-7), 7.39 (br t, J=5.3 Hz, 2H, 2×NH), 7.58 (ddd, J=8.8, 6.6, 1.4 Hz, 2 H, H-7 or H-6), 7.66 (d, J=8.7 Hz, H-2 or H-1), 7.70 (br d, J=7.9 Hz, 2 H, H-5 or H-8), 7.94 (d, J=8.6 Hz, 2H, H-8 or H-5) and 8.37 (s, 2H, H-9). HRMS (FAB⁺) m/z calcd for C₃₇ H₃₈ N₅ O₂ 584.3026 (MH⁺), found 584.3016.

EXAMPLE 7 Preparation of Compound 6 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 5-methylacridine-4-carboxylic acid gave bis[(5-methylacridine-4-carboxamido)propyl]methylamine (6) (53%) as a yellow oil. ¹ H NMR (CDCl₃) δ 1.61 (s, 6 H, 2×CH₃), 1.97-2.00 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.30 (s, 3 H, NCH₃), 2.58 (t, J=7.5 Hz, 4 H, 2×CH₂ NCH₃), 3.70 (q, J=6.5 Hz, 4 H, 2×CH₂ NH), 7.37 (dd, J=8.5, 6.8 Hz, 2 H, H-7), 7.57 (br d, J=6.7 Hz, 2 H, H-8), 7.61 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 7.74 (br d, J=8.6 Hz, 2 H, H-6), 8.03 (dd, J=8.4, 1.5 Hz, 2 H, H-1), 8.69 (s, 2 H, H-9), 8.94 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.79 (br t, J=5.1 Hz, 2 H, 2×NH). HRMS (FAB⁺) m/z calcd for C₃₇ H₃₈ N₅ O₂ 584.3026 (MH⁺), found 584.3044.

EXAMPLE 8 Preparation of Compound 7 of Table I by the Method of Scheme 1

Similar reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-ethyl-9-oxoacridon-4-carboxylic acid as above gave 5-ethylacridine-4-carboxylic acid (79%), mp (acetone) 239-240.5° C. ¹ H NMR [(CD₃)₂ SO] δ 1.43 (t, J=7.5 Hz, 3 H, CH₃), 3.27-3.38 (m, 2 H, CH₂ -obscured by H₂ O), 7.73 (br t, J=7.2 Hz, 1 H, H-2), 7.87 (br t, J=7.8 Hz, 1 H, H-7), 7.93 (br d, J=6.6 Hz, 1 H, H-1), 8.19 (br d, J=8.4 Hz, 1 H, H-6), 8.57 (br d, J=8.2 Hz, 1 H, H-8), 8.76 (br d, J=6.9 Hz, 1 H, H-3), 9.54 (s, 1 H, H-9) and 17.44 (br s, 1, COOH). Anal. (C₁₆ H₁₃ NO₂) C, H, N.

Activation and coupling of this as above gave bis[(5-ethylacridine-4-carboxamido)propyl]-methylamine (7) (57%) as a yellow oil. ¹ H NMR [CDCl₃ ] δ 1.42 (t, J=7.5 Hz, 6 H, 2×CH₃), 1.97-2.04 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.32 (s, 3 H, NCH₃), 2.61 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.24 (q, J=7.5 Hz, 4 H, 2×CH₂ CH₃), 3.69 (q, J=6.2 Hz, 4 H, 2×CH₂ NH), 7.40 (dd, J=8.4, 6.8 Hz, 2 H, H-7), 7.53 (dd, J=6.7 Hz, 1.0, 2 H, H-6), 7.60 (dd, J=8.3, 7.1 Hz, 2 H, H-2), 7.74 (dd, J=8.2, 1.0 Hz, 2 H, H-8), 8.02 (dd, J=8.4, 1.5 Hz, 2 H, H-1), 8.69 (s, 2 H, H-9), 8.93 (dd, J=7.1, 1.6 Hz, 2 H, H-3) and 11.77 (br t, J=5.5 Hz, 2×CONH). HRMS (FAB⁺) m/z calcd for C₃₉ H₄₂ N₅ O₂ 612.3339 (MH⁺), found 612.3343.)

EXAMPLE 9 Preparation of Compound 8 of Table I by the Method of Scheme 1

Similar reaction of 2-iodoisophthalic acid and 2-isopropylaniline gave 2-[(2-isopropyl)phenylamino]-isophthalic acid (38%), mp (EtOAc/petroleum ether) 217-219° C. ¹ H NMR [(CD₃)₂ SO] δ 1.25 (d, J=6.8 Hz, 6 H, 2×CH₃), 3.22-3.29 (m, 1 H, CH), 6.81 (dd, J=7.4, 1.8 Hz, 1 H, H-3' or H-6'), 6.93 (t, J=7.7 Hz, 1 H, H-2), 6.92-7.02 (m, 2 H, H-4' and H-5'), 7.26 (dd, J=7.1, 2.2 Hz, 1 H, H-6' or H-3'), 7.90 (d, J=7.7 Hz, 2 H, H-4 and H-6), 9.69 (s, 1 H, NH), 12.93 (br s, 2 H, 2×COOH). Anal. (C₁₇ H₁₇ NO₄) C, H, N.

Cyclization of this as above gave 5-isopropyl-9-oxoacridan-4-carboxylic acid (91%), mp (H₂ O) 304° C. (dec). ¹ H NMR [(CD₃)₂ SO] δ 1.42 (d, J=6.8 Hz, 6 H, 2×CH₃), 3.29-3.41 (m, 1 H, CH), 7.31-7.40 (m, 2 H, H-2 and H-7), 7.74 (dd, J=7.4, 1.2 Hz, 1 H, H-6), 8.15 (dd, J=8.1, 1.2 Hz, 1 H, H-8), 8.47 (dd, J=7.6, 1.6 Hz, 1 H, H-3), 8.53 (dd, J=8.0, 1.6 Hz, 1 H, H-1), 12.48 (s, 1 H, NH), 14.07 (br s, 1 H, COOH). Anal. (C₁₇ H₁₅ NO₃.0.25 H₂ O). C, H, N.

Reduction of this as above gave 5-isopropylacridine-4-carboxylic acid (70%), mp (acetone) 238° C. (dec). ¹ H NMR [(CD₃)₂ SO] δ 1.45 (d, J=6.8 Hz, 6 H, 2×CH₃), 3.94-4.05 (m, 1 H, CH), 7.75 (dd, J=8.4, 7.1 Hz, 1 H, H-2 or H-7), 7.86 (dd, J=8.4, 7.1 Hz, 1 H, H-7 or H-2), 7.95 (br d, J=6.9 Hz, 1 H, H-6), 8.18 (dd, J=8.4, 1.0 Hz, 1 H, H-8), 8.55 (dd, J=8.4, 1.4 Hz, 1 H, H-1), 8.75 (dd, J=7.1, 1.4 Hz, 1 H, H-3), 9.52 (s, 1 H, H-9), 17.39 (br s, 1 H, COOH). Anal. (C₁₇ H₁₅ NO₂) C, H, N.

Activation and cyclization of this as above gave bis[(5-isopropylacridine-4-carboxamido)-propyl]methylamine (8) (70%) as a foam. ¹ H NMR (CDCl₃) δ 1.47 (d, J=7.0 Hz, 12 H, 4×CH₃), 1.96-2.03 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.32 (s, 3 H, NCH₃), 2.59 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.70 (q, J=7.1, 6.3 Hz, 4 H, 2×CH₂ NH), 4.15-4.18 (m, 2 H, 2×CH), 7.53 (dd, J=8.4, 6.9 Hz, 2 H, H-7), 7.63 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 7.67 (br d, J=6.6 Hz, 2 H, H-6), 7.83 (dd, J=8.4, 1.1 Hz, 2 H, H-8), 8.07 (dd, J=8.3, 1.5 Hz, 2 H, H-1), 8.80 (s, 2 H, H-9), 8.95 (dd, J=7.1, 1.6 Hz, 2 H, H-3), 11.80 (br t, J=5.6 Hz, 2NH). HRMS (FAB⁺) m/z calcd for C₄₁ H₄₆ N₅ O₂ 640.3652 (MH⁺), found 640.3657. Anal. (C₄₁ H₄₅ N₅ O₂) C, H, N.

EXAMPLE 10 Preparation of Compound 9 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 5-phenylacridine-4-carboxylic acid gave bis[(5-phenylacridine-4-carboxamido)propyl]methylamine (9) (64%) as a yellow oil. ¹ H NMR (CDCl₃) δ 1.24-1.26 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.04 (s, 3 H, NCH₃), 2.06-2.10 (br t, J=7.7 Hz, 4 H. 2×CH₂ NCH₃), 3.13 (q, J=7.0, 6.7 Hz, 4 H, 2×CH₂ NH), 7.43-7.45 (m, 2 H, H-4'), 7.49-7.53 (m, 4 H, H-3' and H-5'), 7.59-7.67 (m, 8 H, H-2, H-2', H6', H-7), 7.75 (dd, J=6.7, 1.4 Hz, 2 H, H-6), 7.99 (dd, J=8.5, 1.3 Hz, 2 H, H-8), 8.09 (dd, J=8.4, 1.5 Hz, 2 H, H-1), 8.88 (s, 2 H, H-9), 8.94 (dd, J=7.2, 1.5 Hz, 2 H, H-3), 11.06 (br t, J=6.0 Hz, 2NH). HRMS (FAB⁺) m/z calcd for C₄₇ H₄₂ N₅ O₂ 708.3339 (MH⁺), found 708.3345.

EXAMPLE 11 Preparation of Compound 10 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 5-methoxyacridine-4-carboxylic acid gave bis[(5-methoxyacridine-4-carboxamido)propyl]-methylamine (10) (71%) as a yellow oil. ¹ H NMR (CDCl₃) δ 1.99-2.06 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.72 (t, J=7.6 Hz, 4 H, 2×CH₂ NCH₃), 3.65 (q, J=7.0, 5.2 Hz, 4 H, 2×CH₂ NH), 3.87 (s, 6 H, 2×OCH₃), 6.67 (dd, J=6.5, 2.0 Hz, 2 H, H-6), 7.10-7.16 (m, 4 H, H-7 and H-8), 7.54 (dd, J=8.2, 7.2 Hz, 2 H, H-2), 7.86 (dd, J=8.4, 1.3 Hz, 2 H, H-1), 8.36 (s, 2 H, H-9), 8.82 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 12.04 (br t, J=4.6 Hz, 2 H, 2×CONH). HRMS (FAB⁺) m/z calcd for C₃₇ H₃₈ N₅ O₄ 616.2924 (MH⁺), found 616.2943.

EXAMPLE 12 Preparation of Compound 11 of Table I by the Method of Scheme 1

Reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-fluoro-9-oxoacridan-4-carboxylic acid as above gave 5-fluoroacridine-4-carboxylic acid (90%), mp (MeOH/H₂ O) 295-298° C. (dec). ¹ H NMR [(CD₃)₂ SO] δ 7.74-7.80 (m, 1 H, ArH), 7.90-7.96 (m, 2 H, ArH), 8.19 (d, J=8.6 Hz, 1 H, ArH), 8.61 (dd, J=8.6, 1.2 Hz, 1 H. ArH), 8.81 (dd, J=7.0, 1.0 Hz, 1 H, ArH), 9.65 (s, 1 H, H-9). Anal. (C₁₄ H₈ FNO₂) C, H, N, F.

Activation and coupling of this as above gave bis[(5-fluoroacridine-4-carboxamido)propyl]-methylamine (11) (96%), mp (HCl salt) 188° C. (dec). ¹ H NMR (CDCl₃) δ 2.06 (quin, J=7.2 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, CH₃), 2.73 (t, J=7.6 Hz, 4 H, 2×CH₂ NCH₃), 3.72 (q, J=6.3 Hz, 4 H, 2×CH₂ NH), 7.26 (m, 4 H, ArH), 7.56 (m, 2 H, ArH),7.59 (dd, J=8.4, 7.2 Hz, 2 H, H-2), 7.99 (dd, J=8.4 1.4 Hz, 2 H, H-1), 8.64 (d, J=0.6 Hz, 2 H, H-9), 8.93 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.61 (t, J=4.57 Hz, 2 H CONH).

EXAMPLE 13 Preparation of Compound 12 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 5-chloroacridine-4-carboxylic acid gave bis[(5-chloroacridine-4-carboxamido)propyl]methylamine (12) (62%) as a yellow oil. ¹ H NMR (CDCl₃) δ 2.01-2.05 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.33 (s, 3 H, NCH₃), 2.64 (t, J=7.5 Hz, 4 H, 2×CH₂ NCH₃), 3.72 (q, J=6.4, Hz, 4 H, 2×CH₂ NH), 7.33 (dd, J=8.4, 7.3 Hz, 2 H, H-7), 7.58 (dd, J=8.2, 7.2 Hz, 2 H, H-2), 7.74-7.77 (m, 4 H, H-6 and H-8), 7.96 (dd, J=8.4, 1.5 Hz, 2 H, H-1), 8.64 (s, 2 H, H-9), 8.91 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.74 (br t, J=5.3 Hz, 2 H, 2×NH). HRMS (FAB⁺) m/z calcd for C₃₅ H₃₂ ³⁵ Cl₂ N₅ O₂ 624.1933 (MH⁺), found 624.1940.

EXAMPLE 14 Preparation of Compound 13 of Table I by the Method of Scheme 1

Reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-bromo-9-oxoacridan-4-carboxylic acid as above gave 5-bromoacridine-4-carboxylic acid (70%), mp (MeOH/H₂ O) 327° C. (dec). ¹ H NMR [(CD₃)₂ SO] δ 7.71 (dd, J=8.3, 7.4 Hz, 1 H, H-2), 7.94 (dd, J=8.4, 7.1 Hz, 1 H, H-7), 8.40 (dd, J=8.7, 0.8 Hz, 1 H, ArH), 8.50 (dd, J=7.3, 1.0 Hz, 1 H, ArH), 8.64 (dd, J=8.3, 1.3 Hz, 1 H, ArH), 8.85 (dd, J=7.1, 1.3 Hz, 1 H, ArH), 9.66 (s, 1 H, H-9), 16.77 (br s, 1 H, COOH). Anal. (C₁₄ H₈ BrNO₂) C, H, N, Br.

Activation and coupling of this as above gave bis[(5-bromoacridine-4-carboxamido)propyl]-methylamine (13) (80%), mp (HCl salt) 212-214° C. ¹ H NMR (CDCl₃) δ 2.05 (quin, J=7.3 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.33 (s, 3 H, CH₃), 2.63 (t, J=7.6 Hz, 4 H, 2×CH₂ NCH₃), 3.73 (q, J=6.7 Hz, 4 H, 2×CH₂ NH), 7.28 (dd, J=8.2, 7.2 Hz, 2 H, H-2), 7.57 (dd, J=8.4, 7.2 Hz, 2 H, H-7), 7.81 (dd, J=8.5, 0.9 Hz, 2 H, H-1), 7.91 (m, 4 H, ArH), 8.64 (s, 2 H, H-9), 8.90 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.72 (t, J=5.6 Hz, 2 H,).

EXAMPLE 15 Preparation of Compound 15 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 6-methoxyacridine-4-carboxylic acid gave bis[(6-methoxyacridine-4-carboxamido)propyl]-methylamine (15) (24%), mp (HCl salt) 204-206° C. (dec). ¹ H NMR (CD₃)₂ SO] δ 2.20 (m, 4 H, 2×CH₂ CH₂ CH₂) 2.85 (d, J=4.65 Hz, 3 H, CH₃), 3.59-3.69 (m, 8 H, 4×CH₂), 3.95 (s, 6 H, 2×OCH₃), 7.17 (d, J=8.9 Hz, 1 H, ArH), 7.57 (br s, 1 H, ArH), 7.64 (t, J=7.7 Hz, 1 H, H-2), 7.70 (d, J=0.8 Hz, 1 H, H-5), 7.97 (d, J=8.35 Hz, 1 H, ArH), 8.25 (d, J=8.35 Hz, 1 H), 8.63 (d, J=6.55 Hz, 1 H, ArH), 9.11 (s, 1 H, H-9), 10.74 (br s, 1 H, NH), 11.21 (br s, 2 H, 2×CONH), 14.43 (br s, 1 H, NH).

EXAMPLE 16 Preparation of Compound 16 of Table I by the Method of Scheme 1

Reduction of 6-fluoro-9-oxoacridan-4-carboxylic acid as above gave 6-fluoroacridine-4-carboxylic acid (91%), mp (MeOH/H₂ O) 268-270° C. ¹ H NMR [(CD₃)₂ SO] δ 7.76 (td, J=8.9, 2.5 Hz, 1 H, H-7), 7.86 (td, J=8,9, 2.5 Hz, 1 H, H-2), 8.21 (dd, J=10.6, 2.4 Hz, 1 H, H-6), 8.45 (dd, J=9.3, 6.4 Hz, 1 H, H-1), 8.58 (dd, J=8.4 , 1.3 Hz, 1 H, ArH), 8.77 (dd, J=7.1, 1.5 Hz, 1 H, ArH), 9.60 (s, 1 H, H-9), 16.67 (br s, 1 H, COOH).

Activation and coupling of this as above gave bis[(6-fluoroacridine-4-carboxamido)propyl]-methylamine (16) (57%), mp (HCl salt) 165.5° C. (dec). ¹ H NMR (CDCl₃) δ 2.04 (quin, J=7.1 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.39 (s, 3 H. CH₃) 2.72 (t, J=7.4 Hz, 6 H, 2×CH₂ NCH₃), 3.45 (q, J=6.4 Hz, 4 H. 2×CH₂ NH), 7.28 (ddd, J=9.2, 8.0, 2.4 Hz, 2 H, H-2), 7.62 (dd, J=8.35, 7.2 Hz, 2 H, H-7), 7.69 (dd, J=7.6, 2.4 Hz, 2 H, H-3), 7.89 (dd, J=9.2, 6.1 Hz, 2 H, H-8), 8.05 (dd, J=8.3, 1.5 Hz, 2 H, H-1), 8.74 (s, 2 H, H-9), 8.95 (dd, J=7.2, 1.5 Hz, 2 H, H-5), 11.57 (t, J=4.85 Hz, 2 H, 2×CONH). Anal. (C₃₅ H₃₁ F₂ N₅ O₂.HCl.4H₂ O) C, H, N,

EXAMPLE 17 Preparation of Compound 17 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 6-chloroacridine-4-carboxylic acid gave bis[(6-chloroacridine-4-carboxamido)propyl]methyl-amine (17) (76%), mp (HCl salt) 216-218° C. ¹ H NMR (CD₃)₂ SO] δ 2.17 (quin, J=6.9 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.87 (d, J=4.7 Hz, 3 H, CH₃), 3.30 (m, 4 H, 2×CH₂), 3.63 (m, 4 H, 2×CH₂), 7.47 (dd, J=8.9, 2.0 Hz, 1 H, ArH), 7.69 (t, J=7.7 Hz, 1 H, ArH), 8.06 (d, J=9.0 Hz, 1 H, H-8), 8.28 (dd, J=8.3, 1.3 Hz, 1 H, ArH), 8.38 (d, J=1.7 Hz, 1 H, H-5), 8.64 (dd, J=7.1, 1.3 Hz, 1 H, ArH) 9.16 (s, 1 H, H-9), 10.17 (br s, 1 H, NH), 11.09 (t, J=5.7 Hz, 2 H, 2×NH), 11.44 (br s, 2 H, 2×CONH).

EXAMPLE 18 Preparation of Compound 21 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 7-methylacridine-4-carboxylic acid gave bis[(7-methylacridine-4-carboxamido)propyl]methyl-amine (21) (73%) as a yellow oil. ¹ H NMR (CDCl₃) δ 2.03-2.10 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.34 (s, 6 H, 2×CH₃), 2.39 (s, 3 H, NCH₃), 2.80 (t, J=7.6 Hz, 4 H, 2×CH₂ NCH₃), 3.73 (q, J=6.1 Hz, 4 H, 2×CH₂ NH), 7.30 (br s, 2 H, H-8), 7.35 (dd, J=8.8, 1.9 Hz, 2 H, H-6), 7.55 (dd, J=8.4, 7.1 Hz, 2 H, H-2), 7.77 (d, J=8.9 Hz, 2 H, H-5), 7.92 (dd, J=8.4, 1.5 Hz, 2 H, H-1), 8.36 (s, 2 H, H-9), 8.84 (dd, J=7.1, 1.5 Hz, 2H, H-3), 11.74 (br t, J=5.0 Hz, 2 H, 2×CONH. HRMS (FAB⁺) m/z calcd for C₃₇ H₃₈ N₅ O₂ 584.3026 (MH⁺), found 584.3043.

EXAMPLE 19 Preparation of Compound 23 of Table I by the Method of Scheme 1

Similar reaction of 2-iodoisophthalic acid and 4-isopropylaniline gave 2-[(4-isopropyl)phenylamino]isophthalic acid (62%), mp (EtOAc/petroleum ether) 208° C. (dec). ¹ H NMR [(CD₃)₂ SO] δ 1.16 (d, J=6.9 Hz, 6 H, 2×CH₃), 2.78-2.82 (m, 1 H, CH), 6.83 (d, J=8.4 Hz, 2 H, H-2' and H-6' or H-3' and H-5'; 6.97 (t, J=7.7 Hz, 1 H, H-5), 7.07 (d, J=8.5 Hz, 2 H, H-3' and H-5' or H-2' and H-6'), 7.92 (d, J=7.7 Hz, 2 H, H-4 and H-6), 9.66 (br s, 1 H, NH), 12.89 (br s, 2 H, 2×COOH). Anal. (C₁₇ H₁₇ NO₄) C, H, N.

Cyclization of this as above gave 7-isopropyl-9-oxoacridan-4-carboxylic acid (95%) mp (H₂ O/MeOH/TEA/AcOH) 289-291° C. ¹ H NMR [(CD₃)₂ SO] δ 1.28 (d, J=6.9 Hz, 6 H, 2×CH₃), 3.03-3.07 (m, 1 H, CH), 7.34 (t, J=7.7 Hz, 1 H, H-2), 7.70 (dd, J=8.6, 1.6 Hz, 1 H, H-6), 7.74 (d, J=8.5 Hz, 1 H, H-5), 8.07 (d, J=1.6 Hz, H-8), 8.43 (dd, J=7.5, 1.6 Hz, 1 H, H-3), 8.54 (dd, J=7.9, 1.6 Hz, 1 H, H-1), 11.93 (s, 1 H, NH), 13.80 (br s, 1 H, COOH). Anal. (C₁₇ H₁₅ NO₃.0.25 H₂ O) C, H, N.

Reduction of this as above gave 7-isopropylacridine-4-carboxylic acid (51%), mp (acetone) 186-187° C. ¹ H NMR [(CD₃)₂ SO] δ 1.37 (d, J=6.9 Hz, 6 H, 2×CH₃), 3.15-3.25 (m, 1 H, CH), 7.84 (dd, J=8.3, 7.2 Hz, 1 H, H-2), 8.03 (dd, J=9.0, 1.8 Hz, 1 H, H-6), 8.11 (br s, 1 H, H-8), 8.27 (d, J=9.0 Hz, 1 H, H-5), 8.54 (dd, J=8.5, 1.0 Hz, 1 H, H-1), 8.73 (dd, J=7.0, 1.2 Hz, 1 H, H-3), 9.45 (s, 1 H, H-9), 17.10 (br s, 1 H COOH). Anal. (C₁₇ H₁₅ NO₂) C, H, N.

Activation and coupling of this as above gave bis[(7-isopropylacridine-4-carboxamido)-propyl]methylamine (23) (73%) as a yellow oil. ¹ H NMR (CDCl₃) δ 1.33 (d, J=6.9 Hz, 12 H, 4×CH₃), 2.04-2.08 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.74 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.03-3.06 (m, 2 H, 2×CH), 3.74 (q, J=6.2 Hz, 4 H, 2×CH₂ NH), 7.58 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 7.60-7.66 (m, 4 H, H-6 and H-8), 8.01 (d, J=9.5 Hz, 2 H, H-5), 8.03 (dd, J=8.3, 1.5 Hz, 2 H, H-1), 8.66 (s, 2 H, H-9), 8.88 (dd, J=7.2, 1.5 Hz, 2 H, H-3), 11.85 (br t, J=5.1 Hz, 2 H, 2×NH). HRMS (FAB⁺) m/z calcd for C₄₁ H₄₆ N₅ O₂ 640.3652 (MH⁺), found 640.3657.

EXAMPLE 20 Preparation of Compound 24 of Table I by the Method of Scheme 1

Similar reaction of 2-iodoisophthalic acid and 4-tert-butylaniline gave 2-[(4-tert-butyl)phenylamino]isophthalic acid (93%), mp (EtOAc/petroleum ether) 221-222° C. ¹ H NMR [(CD₃)₂ SO] δ 1.24 (s, 9 H, 3×CH₃), 6.84 (d, J=8.7 Hz, 2 H, H-2' and H-6' or H-3' and H-5'), 6.99 (t, J=7.7 Hz, 1 H, H-5), 7.21 (d, J=8.6 Hz, 2 H, H-3' and H-5' or H-2' and H-6'), 7.93 (d, J=7.8 Hz, 2 H, H-4 and H-6), 9.65 (br s, 1 H, NH) and 12.99 (br s, 2 H, 2×COOH Anal. (C₁₈ H₁₃ NO₂) C, H, N.

Cyclization of this as above gave 7-tert-butyl-9-oxoacridan-4-carboxylic acid (79%), mp (H₂ O/MeOH) 326-327.5° C. ¹ H NMR [(CD₃)₂ SO] δ 1.37 (s, 9 H, 3×CH₃), 7.34 (t, J=7.8 Hz, 1 H, H-2), 7.74 (d, J=8.8 Hz, 1 H, H-5), 7.88 (dd, J=8.8, 2.3 Hz, 1 H, H-6), 8.19 (d, J=2.4 Hz, 1 H, H-8), 8.43 (dd, J=7.6, 1.6 Hz, 1 H, H-3), 8.53 (dd, J=8.0, 1.6 Hz, 1 H, H-1), 11.96 (s, 1 H, NH) and 13.85 (br s, 1 H, COOH) ) Anal. (C₁₈ H₁₇ NO₃) C, H. N.

Reduction of this as above gave 7-tert-butylacridine-4-carboxylic acid (62%), mp (acetone) 253-253.5° C. ¹ H NMR [(CD₃)₂ SO] δ 1.46 (s, 9 H, 3×CH₃), 7.83 (dd, J=8.4, 7.1 Hz, 1 H, H-2), 8.18 (d, J=1.7 Hz, 1 H, H-8), 8.22 (dd, J=9.2, 2.0 Hz, 1 H, H-6), 8.27 (d, J=9.2 Hz, 1 H, H-5), 8.52 (dd, J=8.4, 1.2 Hz, 1 H, H-1), 8.72 (dd, J=7.1, 1.2 Hz, 1 H, H-3), 9.46 (s, 1 H, H-9) and 17.11 (br s, 1 H, COOH)). Anal. (C₁₈ H₁₇ NO₂) C, H, N.

Activation and coupling of this as above gave bis[(7-tert-butylacridine-4-carboxamido)-propyl]methylamine (24) (82%) as a yellow oil. ¹ H NMR (CDCl₃) δ 1.43 (s, 18 H, 6×CH₃), 2.04-2.07 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.72 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.74 (q, J=6.8, 5.6 Hz, 4 H, 2×CH₂ NH), 7.59 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 7.81 (d, J=2.1 Hz, 2 H, H-8), 7.88 (dd, J=9.2, 2.1 Hz, 2 H, H-6), 8.05 (dd, J=8.3, 1.4 Hz, 2 H, H-1), 8.07 (d, J=9.3 Hz, 2 H, H-S), 8.73 (s, 2 H, H-9), 8.89 (dd, J=7.2, 1.5 Hz, 2 H, H-3) and 11.87 (br t, J=5.1 Hz, 2 H, 2×(CONH)). HRMS (FAB⁺) m/z calcd for C₄₃ H₅₀ N₅ O₂ 668.3965 (MH⁺), found 668.3963.

EXAMPLE 21 Preparation of Compound 25 of Table I by the Method of Scheme 1

Reduction of the known [Denny et al., J. Med. Chem., 1987, 30, 658] 7-phenyl-9-oxoacridan-4-carboxylic acid as above gave 7-phenylacridine-4-carboxylic acid (69%), mp (acetone) 239-241° C. ¹ H NMR [(CD₃)₂ SO] δ 7.49 (t, J=7.3 Hz, 1 H, H-4'), 7.60 (t, J=7.3 Hz, 2 H, H-3' and H-5'), 7.86 (dd, J=8.4, 7.1 Hz, 1 H, H-2), 7.96 (d, J=7.3 Hz, 2 H, H-2' and H-6'), 8.43 (br s, 2 H, H-6 and H-8), 8.58 (dd, J=8.5, 1.2 Hz, 1 H, H-1), 8.64 (br s, 1 H, H-5), 8.74 (br d, J=7.1 Hz, 1 H, H-3), 9.56 (s, 1 H, H-9), 16.93 (br s, 1 H, COOH). Anal. (C₂₀ H₁₃ NO₂) C, H, N.

Activation and coupling of this as above gave bis[(7-phenylacridine-4-carboxamido)-propyl]methylamine (25) (90%), mp (CH₂ Cl₂ /MeOH) 162-163° C. ¹ H NMR (CDCl₃) δ 2.07-2.14 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.42 (s, 3 H, NCH₃), 2.82 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.77 (q, J=6.5, 5.6 Hz, 4 H, 2×CH₂ NH), 7.40-7.52 (m, 4 H, H-2 and H-4' or H-3' and H-5'), 7.48-7.52 (m, 4 H, H-3' and H-5' or H-2 and H-4'), 7.63-7.65 (m, 4 H, H-2' and H-6'), 7.82-7.84 (m, 4 H, H-6 and H-8), 7.87 (dd, J=8.4 ,1.4 Hz, 2 H, H-1), 7.97 (d, J=9.5 Hz, 2 H, H-5), 8.54 (s, 2 H, H-9), 8.80 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.69 (br t, J=5.2 Hz, 2 H, 2NH). HRMS (FAB⁺) m/z calcd for C₄₇ H₄₂ N₅ O₂ 708.3339 (MH⁺), found 708.3351.

EXAMPLE 22 Preparation of Compound 26 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 7-methoxyacridine-4-carboxylic acid gave bis[(7-methoxyacridine-4-carboxamido)propyl]-methylamine (26) (93%) as a yellow oil. ¹ H NMR (CDCl₃) δ 2.02-2.06 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.37 (s, 3 H, NCH₃), 2.74 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.72 (q, J=6.7, 5.6 Hz, 4 H, 2×CH₂ NH), 3.88 (s, 6 H, OCH₃), 6.89 (d, J=2.7 Hz, 2 H, H-8), 7.32 (dd, J=9.3, 2.7 Hz, 2 H, H-6), 7.54 (dd, J=8.2, 7.2 Hz, 2 H, H-2), 7.85 (d, J=9.3 Hz, 2 H, H-5), 7.94 (dd, J=8.4, 1.5 Hz, 2 H, H-1), 8.44 (s, 2 H, H-9), 8.82 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.69 (br t, J=5.1 Hz, 2×CONH). HRMS (FAB⁺) m/z calcd for C₃₇ H₃₈ N₅ O₄ 616.2924 (MH⁺), found 616.2927.

EXAMPLE 23 Preparation of Compound 27 of Table I by the Method of Scheme 1

Reduction of the known [Atwell et al., J. Med. Chem., 1987, 30, 658] 7-fluoro-9-oxoacridan-4-carboxylic acid as above gave 7-fluoroacridine-4-carboxylic acid (95%), mp (MeOH/H₂ O) 267-268° C. ¹ H NMR [(CD₃)₂ SO] δ 7.87 (dd, J=8.4, 7.0 Hz, 1 H, H-2), 8.01 (ddd, J=9.5, 8.5, 2.3 Hz, 1 H, H-6), 8.13 (dd, J=9.3, 2.8 Hz, 1 H, H-8), 8.45 (dd, J=9.6, 5.3 Hz, 1 H, H-5), 8.54 (dd, J=8.5, 1.3 Hz, 1 H, H-1), 8.73 (dd, J=6.9, 1.4 Hz, 1 H, H-3), 9.47 (s, 1 H, H-9), 16. 53 (br s, 1 H, COOH). Anal. (C₁₄ H₈ FNO₂) C, H, N, F.

Activation and coupling of this as above gave bis[(7-fluoroacridine-4-carboxamido)propyl]-methylamine (27) (57%), mp (HCl salt) 173.5° C. (dec). ¹ H NMR (CDCl₃) δ 2.04 (quin, J=7.07 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.73 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.73 (q, J=6.3 Hz, 4 H, 2×CH₂ NH), 7.32 (dd, J=8.6, 2.7 Hz, 2 H, H-8), 7.42 (ddd, J=9.4, 8.1, 2.7 Hz, 4 H, H-6), 7.63 (dd, J=7.7, 7.2 Hz, 2 H, H-2), 7.96 (dd, J=9.1, 4.9 Hz, 2 H, H-5), 7.99 (dd, J=7.7, 1.5 Hz, 2 H, H-1), 8.56 (s, 2 H, H-9), 8.89 (dd, J=7.0, 1.5 Hz, 2 H, H-3), 11.50 (t, J=4.95 Hz, 2 H, 2×CONH).

EXAMPLE 24 Preparation of Compound 28 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 7-chloroacridine-4-carboxylic acid gave bis[(7-chloroacridine-4-carboxamido)propyl]methyl-amine (28) (75%) as a yellow oil. ¹ H NMR (CDCl₃) δ 2.03-2.07 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.75 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.73 (q, J=6.1, Hz, 4 H, 2×CH₂ NH), 7.45 (dd, J=9.2, 2.3 Hz, 2 H, H-6), 7.63-7.67 (m, 4 H, H-2 and H-8), 7.84 (d, J=9.2 Hz, 2 H, H-5), 7.99 (dd, J=8.4, 1.5 Hz, 2 H, H-1), 8.48 (s, 2 H, H-9), 8.93 (dd, J=7.2, 1.5 Hz, 2 H, H-3), 11.42 (br t, J=5.0 Hz, 2×CONH). HRMS (FAB+) m/z calcd for (MH⁺) C₃₅ H₃₂ ³⁵ Cl₂ N₅ O₂ 624.1933, found 624.1923.

EXAMPLE 25 Preparation of Compound 29 of Table I by the Method of Scheme 1

Reduction of 7-bromo-9-oxoacridan-4-carboxylic acid as above gave 7-bromoacridine-4-carboxylic acid (59%), mp (MeOH/H₂ O) 304° C. (dec). ¹ H NMR [(CD₃)₂ SO] δ 7.87(dd, J=8.4, 7.2 Hz, 1 H, H-2), 8.13 (dd, J=9.2, 2.2 Hz, 1 H, H-6), 8.32 (d, J=9.2 Hz, 1 H, H-5), 8.56 (dd, J=8.5, 1.3 Hz, 1 H, H-1), 8.66 (d, J=2.1 Hz, 1 H, H-8), 8.74 (dd, J=7.1, 1.4 Hz, 1 H, H-3), 9.48 (s, 1 H, H-9), 16.49 (s, 1 H, COOH). Anal. (C₁₄ H₈ BrNO₂) C, H, N, Br.

Activation and coupling of this as above gave bis[(7-bromoacridine-4-carboxamido)propyl]-methylamine (29) (25%), mp (HCl salt) 138-142° C. ¹ H NMR (CDCl₃) δ 2.04 (quin, J=7.0 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, CH₃), 2.75 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.73 (q, J=6.3 Hz, 4 H, 2×CH₂ NH), 7.55 (dd, J=9.1, 2.1 Hz, 2 H, H-6), 7.66 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 7.76 (d, J=9.2 Hz, 2 H, H-5), 7.83 (d, J=2.1 Hz, 2 H, H-8), 7.99 (dd, J=8.2, 1.4 Hz, 2 H, H-1), 8.46 (s, 2 H, H-9), 8.94 (dd, 7.0, 1.5 Hz, 2 H, H-3), 11.41 (t, J=4.9 Hz, 2 H, 2×CONH).

EXAMPLE 26 Preparation of Compound 30 of Table I by the Method of Scheme 1

Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 8-methyl-9-oxoacridan-4-carboxylic acid as above gave bis[(8-methylacridine-4-carboxamido)propyl]methylamine (30) as a yellow oil (61%). ¹ H NMR (CDCl₃) δ 2.03-2.10 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.39 (s, 3 H, NCH₃), 2.66 (s, 6 H, 2×CH₃), 2.79 (t, J=7.5 Hz, 4 H, 2×CH₂ NCH₃), 3.74 (q, J=6.2 Hz, 4 H, 2×CH₂ NH), 7.09 (d, J=6.9 Hz, 2 H, H-5 or H-7), 7.49 (dd, J=8.8, 6.8 Hz, 2 H, H-6), 7.62 (dd, J=8.4, 7.1 Hz, 2 H, H-2), 7.83 (d, J=8.7 Hz, 2 H, H-7 or H-5), 8.04 (dd, J=8.3, 1.5 Hz, 2 H, H-1), 8.74 (s, 2 H, H-9), 8.91 (dd, J=7.1, 1.5 Hz, 2 H, H-3) and 11.78 (br t, J=4.8 Hz, 2×CONH); HRMS (FAB⁺) m/z calcd. for C₃₇ H₃₈ N₅ O₂ 584.3026 (MH⁺), found 584.3033. Anal. (C37H37N5O2.0.5H₂ O) C,H,N.

EXAMPLE 27 Preparation of Compound 31 of Table 1 by the Method of Scheme 1

Activation and coupling of the know chloroacridine-4-carboxylic acid gave bis[(8-chloroacridine-4-carboxamido)propyl]methylamine (31) as a yellow oil (88%). ¹ H NMR (CDCl₃) δ 2.04-2.10 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.40 (s, 3 H, NCH₃), 2.84 (t, J=7.4 Hz, 4 H, 2×CHNCH₃), 3.74 (q, J=6.1, Hz, 4 H, 2CH₂ NH), 7.10 (dd, J=7.3, 0.8 Hz, 2 H, H-5 or H-7), 7.33 (dd, J=8.8, 7.3 Hz, 2 H, H-2 or H-6), 7.65 (dd, J=8.3, 7.2 Hz, 2H, H-6 or H-2), 7.73 (d, J=8.7 Hz, 2H, H-7 or H-5), 8.06 (dd, J=8.8, 1.5 Hz, 2 H, H-1), 8.86 (s, 2H, H-9), 8.90 (dd, J=7.2, 1.5 Hz, 2H, H-3) and 11.36 (br t, J=5.0 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z calcd. for C₃₅ H₃₂ ³⁵ Cl₂ N₅ O₂ 624.1933 (MH⁺), found 624.1939. Anal. (C₃₅ H₃₁ Cl₂ N₅ O₂) C, H, N.

EXAMPLE 28 Preparation of Compound 37 of Table 1 by the Method of Scheme 1

Activation and coupling of acridine-2-carboxylic acid gave bis[(acridine-2-carboxamido)propyl]methyl-amine (37) (60%), mp (CH₂ Cl₂ /petroleum ether) 199-200° C. ¹ H NMR (CDCl₃) δ 1.85-1.91 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.36 (s, 3 H, NCH₃), 2.59 (t, J=6.2 Hz, 4 H, 2×CH₂ NCH₃), 3.65 (dd, J=6.3, 5.9 Hz, 4 H, 2×CH₂ NH), 7.41 (ddd, J=8.4, 6.6, 1.0 Hz, 2 H, H-6 or H-7), 7.64 (br t, J=5.3 Hz, 2 H, 2×NH), 7.70 (ddd, J=8.9, 6.6, 1.4 Hz, 2H, H-7 or H-6), 7.75 (d, J=8.1 Hz, 2 H, H-5 or H-8), 8.06 (dd, J=9.1, 1.9 Hz, 2 H, H-3), 8.13 (dd, J=8.9, 0.8 Hz, 2 H, H-8 or H-5), 8.20 (d, J=9.1 Hz, 2 H, H-4), 8.36 (d, J=1.9 Hz, 2 H, H-1) and 8.52 (s, 2 H, H-9). HRMS (FAB+) m/z calcd. for C₃₅ H₃₄ N₅ O₂ 556.2713 (MH⁺), found 556.2694. Anal. C₃₅ H₃₃ N₅ O₂) C, H, N.

EXAMPLE 29 Preparation of Compound 33 of Table 1 by the Method of Scheme 2

A solution of methyl 2-[N-(2-carboxyphenyl)amino]benzoate [Rewcastle and Denny, Synth. Comm., 1987, 17, 309] (10 g, 36.9 mmol) in dry THF (200 mL) was treated with CDI (8.97 g, 55.4 mmol). The reaction mixture was allowed to stir at room temperature for 1 h, then added slowly to a suspension of NaBH₄ (7.00 g) in H₂ O (200 mL) without isolation of the intermediate imidazolide. When the reaction was observed to be complete (tlc; ca. 30 min), the mixture was quenched with conc. HCl and partitioned between CH₂ Cl₂ (200 mL) and NaHCO₃ (200 mL), and the organic layer was dried with Na₂ SO₄. Removal of the solvent and filtration of the residue through a plug of flash-grade silica gel in petroleum ether/EtOAc (4:1) gave methyl 2-[N-(2-hydroxymethyl)phenylamino]benzoate, (7.85 g, 83%), mp (CH₂ Cl₂ /petroleum ether) 69.0-71.0° C. ¹ H NMR (CDCl₃) δ 1.93 (br s, 1 H, OH), 3.91 (s, 3 H, COOCH₃), 4.72 (s, 2 H, CH₂ OH), 6.74 (ddd, J=8.0, 7.0, 1.1 Hz, 1 H, H-5), 7.08-7.44 (m, 6 H, H-3,3',4,4',5',6'), 7.97 (dd, J=8.0, 1.6 Hz, 1 H, H-6), 9.59 (br s, 1 H, NH). Anal. (C₁₅ H₁₄ NO₃) C, H, N.

A stirred solution of the above alcohol (7.74 g, 30 mmol) in acetone (200 mL) was treated with a suspension of MnO₂ (10 g) at room temperature for 3 days, when all the starting material had been consumed (tlc). The MnO₂ was filtered off (Celite) and the acetone removed under reduced pressure to yield methyl 2-[N-(2-formyl)phenylamino]benzoate as a bright yellow solid (7.70 g, 100%). A sample crystallized from (EtOAc/petroleum ether had mp 110.0-112.0° C. ¹ H NMR (CDCl₃) δ 3.95 (s, 3 H, COOCH₃), 6.95-7.03 (m, 2 H, H-4',5), 7.41-7.45 (m, 2 H, H-5',6), 7.50 (br d, J=8.5 Hz, 1 H, H-3 or H-6'), 7.61 (br d, J=8.2 Hz, 1 H, H-6' or H-3), 7.65 (dd, J=7.7, 1. 7 Hz, 1 H, H-3'), 8.01 (dd, J=7.9, 1.7 Hz, 1 H, H-6), 10.00 (s, 1 H, CHO), 11.26 (br s, 1 H, NH). Anal. (C₁₅ H₁₃ NO₃) C, H, N.

The above aldehyde (210 mg, 0.8 mmol) was placed in a two-necked flask which was then flushed with N₂, trifluoroacetic acid (10 mL) was added, and the solution was stirred for 15 hours at room temperature under N₂. The trifluoroacetic acid was then removed under reduced pressure, and the flask containing the resultant crude methyl acridine-4-carboxylate was flushed with nitrogen. A degassed 2 M solution of NaOH in aqueous EtOH (1:1) (35 mL) was then added, and the mixture was stirred for 3 h at 50° C. under N₂ until a clear solution was obtained, then neutralized with glacial AcOH and extracted with EtOAc (3×50 mL). Evaporation of the organic layer and chromatography of the residue on silica gel, eluting with EtOAc/petroleum ether (1:4) gave acridine-4-carboxylic acid (160 mg, 87%) mp (Me₂ CO) 196-197° C. [Atwell et al., J. Med. Chem. 1987, 30, 664 record mp 202-204° C.

#Dilution of the residue at this point with CH₂ Cl₂ and careful neutralization of the solution with Et₃ N, followed by removal of solvent under reduced pressure and filtration of the residue was through a short column of flash silica gel in EtOAc/petroleum ether (1.3) gave pure methyl acridine-4-carboxylate as an orange oil. ¹ H NMR (CDCl₃) δ 4.12 (s, 3 H, COOCH₃), 7.53-7.58 (m, 2 H, H-2 and H-6 or H-7), 7.79 (ddd, J=8.8, 6.6, 1.4 Hz, 1 H, H-7 or H-6), 8.00 (dd, J=8.0, 1.0 Hz, 1 H, H-1), 8.12-8.14 (m, 2 H, H-5,8), 8.30 (dd, J=8.7, 0.9 Hz, 1 H, H-3), 8.80 (s, 1 H, H-9).

A suspension of acridine-4-carboxylic acid (4.00 g, 17.9 mmol) in DMF (25 mL) was treated with CDI (3.49 g, 21.5 mmol) and stirred at 30° C. for 2 h. After cooling, the mixture was diluted with CH₂ Cl₂ (25 mL) followed by petroleum ether (75 mL) to complete precipitation of product, which was collected, washed with petroleum ether/CH₂ Cl₂ (4:1) and dried to give the moisture sensitive imidazolide (3.81 g, 78%). This was reacted with N,N-bis(3-aminopropyl)methylamine following the procedure described above. The product was purified by chromatography on alumina-90, eluting with CH₂ Cl₂ /MeOH (20:1) to give bis[(acridine-4-carboxamido)propyl]methylamine (33) 83%) as a foam. ¹ H NMR [(CD₃)₂ SO] δ 9.06 (s, 2 H, H-9), 8.65 (d, J=7.1 Hz, 2 H, H-3), 8.24 (d, J=8.5 Hz, 2 H, ArH), 8.00 (t, J=9.5 Hz, 4 H, ArH), 7.8-7.6 (m, 4 H, ArH), 7.45 (t, J=7.5 Hz, 2 H, ArH), 3.58 (q, J=6.2 Hz, 4 H, 2×NHCH₂), 2.65 (t, J=7.0 Hz, 4 H, 2×CH₂ NCH₃), 2.29 (s, 3 H, CH₃), 1.91 (quint, J=6.9 Hz, 4 H, 2×CH₂ CH₂ CH₂). Crystallization from MeOH/EtOAc/HCl gave the trihydrochloride salt, mp 168-170° C. Anal. (C₃₅ H₃₃ N₅ O₂.3HCl) C,H,N,Cl.

EXAMPLE 30 Preparation of Compound 34 of Table 1 by the Method of Scheme 2

Reaction of acridine-4-carboxylic acid imidazolide with N,N-bis(2-aminoethyl)amine as above, followed by crystallization of the crude product from MeOH/H₂ O, gave bis[2-(acridine-4-carboxamido)ethyl]amine (34) (84%). ¹ H NMR [(CD₃)₂ SO] δ 11.57 (t, J=5.0 Hz, 2 H, 2×CONH), 8.80 (s, 2 H, H-9), 8.46 (d, J=7.1 Hz, 2 H, H-3), 8.08 (d, J=8.4 Hz, 2 H, ArH), 7.92 (d, J=8.7 Hz, 2 H, ArH), 7.79 (d, J=8.1 Hz, 2 H, ArH), 7.55 (t, J=7.7 Hz, 2 H, ArH), 7.41 (t, J=7.6 Hz, 2 H, ArH), 7.27 (t, J=7.4 Hz, 2 H, ArH), 3.73 (q, J=5.5 Hz, 4 H, 2×NHCH₂), 3.11 (t, J=5.6 Hz, 4 H, CH₂ NHCH₂). The trihydrochloride salt crystallized from MeOH/EtOAc/HCl, mp 182-184° C. Anal. (C₃₂ H₂₇ N₅ O₂.3HCl) C, H, N, Cl.

EXAMPLE 31 Preparation of Compound 35 of Table 1 by the Method of Scheme 2

Similar reaction of acridine-4-carboxylic acid imidazolide with N,N-bis(3-aminopropyl)amine as above, followed by purification of the product by chromatography on alumina-90, eluting with CH₂ Cl₂ /MeOH (20:1), gave bis[3-(acridine-4-carboxamido)propyl]amine (35) (80%) as an oil. ¹ H NMR [(CD₃)₂ SO] δ 11.40 (t, J=5.4 Hz, 2 H, 2×CONH), 9.19 (s, 2 H, H-9), 8.71 (d, J=7.1 Hz, 2 H, H-3), 8.32 (d, J=8.5 Hz, 2 H, ArH), 8.18-8.00 (m, 4 H, ArH), 7.83-7.62 (m, 4 H, ArH), 7.51 (t, J=7.5 Hz, 2H, ArH), 3.64 (q, J=6.0 Hz, 4H, 2×CONHCH₂) 2.86 (t, J=6.7 Hz, 4H, CH₂ NHCH₂) 1.92 (quint, J=6.5 Hz, 4 H, 2×CH₂ CH₂ CH₂). Crystallization from MeOH/EtOAc/HCl gave the trihydrochloride salt, mp 171-173° C. Anal. (C₃₄ H₃₁ N₅ O₂.2HCl.2H₂ O) C, H, N, Cl.

EXAMPLE 32 Preparation of Compound 36 of Table 1 by the Method of Scheme 2

Similar reaction of acridine-4-carboxylic acid imidazolide with 1,4-bis(3-aminopropyl)piperazine as above, and crystallization of the crude product from CH₂ Cl₂ /EtOAc/iPr₂ O, gave N¹,N4-bis[(acridine-4-carboxamido)propyl]piperazine (36) (91%). ¹ H NMR [(CD₃)₂ SO] δ 11.39 (t, J=5.2 Hz, 2 H, 2×CONH), 9.33 (s, 2 H, H-9), 8.73 (d, J=7.0 Hz, 2 H, H-3), 8.38 (d, J=8.5 Hz, 2 H, ArH), 8.32-8.20 (m, 4 H, ArH), 7.97 (t, J=7.8 Hz, 2 H, ArH), 7.82-7.63 (m, 4 H, ArH), 3.57 (q, J=6.0 Hz, 4 H, 2×NHCH₂), 2.6-2.3 t (m, 12 H, H-piperazine, 2×CH₂ CH₂ CH₂ N), 1.85 (quint, J=6.7 Hz, 4 H, CH₂ CH₂ CH₂). Crystallization from MeOH/EtOAc/HCl gave the tetrahydrochloride salt, mp 248-253° C. Anal. (C₃₈ H₃₈ N₆ O₂.4HCl) C, H, N, Cl.

EXAMPLE 33 Preparation of Compound 18 of Table 1 by the Method of Scheme 2

Reaction of methyl 2-iodobenzoate and 4-bromoanthranilic acid by the reported method [Rewcastle and Denny, Synth. Comm, 1987, 17, 309] gave 4-bromo-2-[(2-methoxycarbonyl-phenyl)amino]benzoic acid (70%), mp (MeOH/H₂ O) 218-219.5° C. ¹ H NMR [(CD₃)₂ SO] δ 3.85 (s, 3 H, COOCH₃), 7.08-7.12 (m, 2 H, 2×ArH), 7.50 (d, J=1.9 Hz, 1 H, H-3), 7.57 (d, J=3.8 Hz, 3 H, 2×ArH), 7.84 (d, J=8.4 Hz, 1 H, ArH), 7.93 (d, J=7.7 Hz, 1 H, ArH), 10.80 (s, 1 H, NH), 13.33 (br s, 1 H, COOH). Anal. (C₁₅ H₁₂ BrNO₄) C, H, N.

Formation of the imidazolide and reduction of this as above gave crude methyl-2-[N-(5-bromo-2'-hydroxymethyl)phenylamino]benzoate (81%). ¹ H NMR [(CD₃)₂ SO] δ 3.91 (s, 3 H, COOCH₃), 4.68 (d, J=4.8 Hz, 2 H, CH₂), 6.79-6.84 (m, 1 H, ArH), 7.17-7.21 (m, 2 H, 2×ArH), 7.25 (d, J=8.5 Hz, 1 H, ArH), 7.40-7.43 (m, 2 H, ArH), 7.55 (d, J=1.8 Hz, 1 H, H-6'), 9.66 (s, 1 H, NH). Oxidation of this as above gave methyl 2-[N-(5'-bromo-2'-formyl)phenylamino]-benzoate (67% over two steps), mp (MeOH/H₂ O) -122-123° C. ¹ H NMR [(CD₃)₂ SO] δ 3.95 (s, 3 H, CO₂ CH₃), 7.05-7.11 (m, 2 H, ArH), 7.41-7.52 (m, 2 H, 2×ArH), 7.58-7.62 (m, 2 H, 2×ArH), 8.03 (dd, J=7.9, 1.6 Hz, 1 H, ArH), 9.93 (s, 1 H, CH), 11.33 (br s, 1 H, NH). Anal. (C₁₅ H₁₂ BrNO₃) C, H, N.

Cyclization of this as above gave crude methyl 6-bromoacridine-4-carboxylate, which was immediately hydrolyzed as above to give 6-bromoacridine-4-carboxylic acid (100% over two steps), mp (MeOH/H₂ O) 283-285° C. ¹ H NMR [(CD₃)₂ SO] δ 7.87 (dd, J=8.3, 7.15 Hz, 1 H, H-2), 7.99 (dd, J=9.0, 1.9 Hz, 1 H, H-7), 8.23 (d, J=9.1 Hz, 1 H, H-8), 8.56 (dd, J=8.4, 1.4 Hz, 1 H , H-1), 8.70 (s, 1 H, H-5), 8.73 (dd, J=7.06, 1.4 Hz, H-4), 9.57 (s, 1 H, H-9), 16.44 (br s, 1 H, COOH). Anal. (C₁₄ H₈ BrNO₂) C, H, N.

Activation and coupling of this as above gave bis[(6-bromoacridine-4-carboxamido)propyl]-methylamine (18) (91%), mp (HCl salt) 218-221° C. ¹ H NMR (CDCl₃) δ 2.07(quin, J=7.0 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.41 (s, 3 H, CH₃), 2.76 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.75 (q, J=6.4 Hz, 4 H, 2×CH₂ NH), 7.42 (dd, J=8.95, 1.8 Hz, 2 H, ArH), 7.65 (m, 4 H, ArH), 8.03 (dd, J=8.4, 1.5 Hz, 2 H, ArH), 8.25 (d, J=0.9 Hz, H-5), 8.67 (s, 2 H, H-9), 8.95 (dd, J=7.15, 1.5 Hz, 2 H, ArH), 11.45 (t, J=5.0 Hz, 2 H, CONH).

EXAMPLE 34 Preparation of Compound 14 of Table 1 by the Method of Scheme 2

Similar reaction of 2-amino-3-trifluoromethylbenzoic acid and methyl-2-iodobenzoate by the reported method [Rewcastle and Denny, Synth. Comm, 1987, 17, 309] gave 3-trifluoromethyl-2-[(2-methoxycarbonyl)phenyl)amino]benzoic acid (51%), mp (MeOH/H₂ O) 113-115° C. ¹ H NMR [(CD₃)₂ SO] δ 3.89 (s, 3 H, CO₂ CH₃), 6.35 (d, J=8.5 Hz, 1 H, ArH), 6.78 (t, J=7.5 Hz, 1 H, ArH), 7.30 (ddd, J=7.8, 7.8, 1.6 Hz, 1 H, ArH), 7.59 (t, J=7.8 Hz, 1 H, ArH), 7.88 (dd, J=8.0, 1.5 Hz, 1 H, ArH), 8.03 (d, J=7.4 Hz, 1 H, ArH), 8.07 (d, J=8.07 Hz, 1 H, ArH), 9.49 (s, 1 H, NH), 13.15 (br s, 1 H, COOH). Anal. (C₁₆ H₁₂ F₃ NO₂) C, H, N, F.

Formation of the corresponding imidazolide and immediate reduction of this as above gave crude methyl-2-[N-(2-hydroxymethyl-6-trifluoromethyl)phenylamino]benzoate (100%) as an oil. ¹ H NMR [(CD₃)₂ SO] δ 3.94 (s, 3 H, CO₂ CH₃), 4.50 (d, J=14.0 Hz, 1 H, CH), 4.72 (d, J=14.0 Hz, 1 H. CH), 6.18 (dd, J=8.6, 0.7 Hz, 1 H, ArH), 6.72 (ddd, J=7.7, 7.5, 1.0 Hz, 1 H, ArH), 7.23 (ddd, J=8.5, 7.1, 1.5 Hz, 1 H, ArH), 7.46 (t, J=7.8 Hz, 1 H, ArH), 7.70 (d, J=7.1 Hz, 1 H, ArH), 7.83 (d, J=7.7 Hz, 1 H, ArH), 7.98 (dd, J=8.0, 1.6 Hz , 1 H, ArH), 9.25 (s, 1 H, NH).

A solution of the above crude ester was oxidized as above to give methyl 2-[N-(6-trifluoromethyl-2-formyl)phenylamino]benzoate (100%), mp (MeOH/H₂ O) 122-123° C. ¹ H NMR (CDCl₃) δ 3.96 (s, 3 H, CO₂ CH₃), 6.49 (dd, J=8.3, 0.8 Hz, 1 H, ArH), 6.79 (td, J=7.5, 1.0 Hz, 1 H, ArH), 7.25 (ddd, J=8.3, 6.5, 1,6 Hz, 1 H, ArH), 7.50 (t, J=7.8 Hz, 1 H, ArH), 7.9-8.01 (m, 2 H, 2×ArH), 8.14 (dd, J=7.8, 1.4 Hz, 1 H, ArH), 9.71 (br s, 1 H, CHO), 10.09 (s, 1 H, NH). Anal. (C₁₆ H₁₂ F₃ NO₃) C, H. N).

Cyclization of this, followed by hydrolysis as above, gave 5-trifluoromethylacridine-4-carboxylic acid (76%), mp (MeOH/H₂ O) 287-288.5° C. ¹ H NMR δ 7.89-7.98 (m, 2 H, 2×ArH), 8.55 (d, J=7.0 Hz, 1 H, ArH), 8.65 (td, J=8.7, 1.3 Hz, 2 H, 2×ArH), 8.86 (dd, J=6.9, 1.4 Hz, 1 H, ArH), 9.74 (s, 1 H, H-9), 16.13 (br s, 1 H, COOH). Anal. (C₁₈ H₈ F₃ NO₄) C, H, N.

Activation and coupling of this as above gave bis[(5-trifluoromethylacridine-4-carboxamido)propyl]-methylamine (14) (52%), mp (EtOAc/MeOH) 231-233° C. ¹ H NMR [(CD₃)₂ SO] δ 1.81 (quin, J=7.1 Hz, 4 H, CH₂ CH₂ CH₂), 2.42 (s, 3 H, NCH₃), 2.44 (t, J=7.1 Hz, 4 H, CH₂ NH₃), 3.51 (q , J=6.8 Hz, 4 H, NHCH₂ CH₂), 7.73 (q, J=7.4 Hz, 4 H,4×ArH), 8.24-8.29 (m, 4 H, 4×ArH), 8.42 (d, J=8.1 Hz, 2 H, ArH), 8.78 (dd, J=7.1, 1.5 Hz, 2 H, ArH), 9.30 (s, 2 H, H-9), 10.97 (t, J=5.8 Hz, 2 H, CONH). Anal. (C₃₇ H₃₁ F₆ N₅ O₂.3HCl.2H₂ O) C, H, N).

EXAMPLE 35 Preparation of Compound 19 of Table 1 by the Method of Scheme 2

Reaction of 4-trifluoromethylanthranilic acid and methyl 2-iodobenzoate by the reported method [Rewcastle and Denny, Synth, Comm 1987, 17, 309 gave 4-trifluoromethyl-2-(2-methoxycarbonylphenyamino)benzoic acid (43%), mp (MeOH/H₂ O) 206-207° C. ¹ H NMR [(CD₃)₂ SO] δ 3.87 (s, 3 H, CO₂ CH₃), 7.12 (ddd, J=8.0, 6.1, 2.1 Hz, 1 H., H-5'), 7.23 (dd, J=8.3, 1.0 Hz, 1 H, ArH), 7.55-7.62 (m, 3 H, 3×ArH), 7.95 (dd, J=8.0, 1.3 Hz, 1 H, ArH), 8.12 (d, J=8.2 Hz, 1 H, ArH). Formation of the corresponding imidazolide and immediate reduction of this as above gave methyl-2-[N-(5'-trifluoromethyl-2'-hydroxymethyl)phenyl-amino]benzoate (86%), mp (hexane) 86-87° C. ¹ H NMR (CDCl₃) δ 2.00 (t, J=5.6 Hz, 1 H, OH), 3.92 (s, 3 H, CO₂ CH₃), 4.78(d, J=5.3 Hz, 2 H, CH₂), 6.84 (td, J=7.6, 1.1 Hz, 1 H, ArH), 7.15 (dd, J=8.6, 0.8 Hz, 1 H, ArH), 7.31-7.39 (m, 2 H, 2×ArH), 7.52 (d, J=7.7 Hz, 1 H, ArH), 7.70 (s, 1 H, H-6'), 8.76 (dd, J=8.0, 1.6 Hz, 1 H, ArH), 9.72 (s, 1 H, NH).

Oxidation of this as above gave methyl-2-[N-(5'-trifluoromethyl-2'-formyl)phenylamino]-benzoate (85%), mp (MeOH/H₂ O) 79.5-80.5° C. ¹ H NMR [(CD₃)₂ SO] δ 3.86 (s, 3 H, CO₂ CH₃), 7.20 (ddd, J=8.0, 6.2, 2.0 Hz, 1 H, ArH), 7.34 (dd, J=7.5, 0.8 Hz, 1 H, ArH), 7.60-7.66 (m, 3 H, 3×ArH), 7.98 (dd, J=8.0, 1.4 Hz, 1 H, ArH), 8.09 (d, J=8.0 Hz, 1 H, ArH), 10.09 (s, 1 H, NH), 11.16 (s, 1 H, CHO).

Cyclization of this as above, followed by immediate hydrolysis of the crude methyl 6-trifluoromethylacridine-4-carboxylate, gave 6-trifluoromethylacridine-4-carboxylic acid (81%), mp (MeOH/H₂ O) 244-246° C. ¹ H NMR [(CD₃)₂ SO] δ 7.93 (t, J=7.9 Hz, 1 H, H-3), 7.98 (dd, J=8.9, 1.5 Hz, 1 H, ArH), 8.56 (d, J=8.8 Hz, 1 H, ArH), 8.60 (d, J=8.5 Hz, 1 H, ArH), 8.79 (dd, J=7.0, 1.1 Hz, 1 H, ArH), 8.86 (s, 1 H, H-5), 9.66 (s, 1 H, H-9).

Activation and coupling of this as above gave bis[(6-trifluoromethylacridine-4-carboxamido)propyl]-methylamine (19) (60%), mp (hexane) 169-171° C. ¹ H NMR [(CD₃)₂ SO] δ 1.89 (quin, J=6.6 Hz, 4 H, CH₂ CH₂ CH₂), 2.28 (s, 3 H, NCH₃), 2.66 (t, J=6.8 Hz, 4 H, CH₂ CH₃), 3.56 (q , J=6.1 Hz, 4 H. NHCH₂ CH₂), 7.60 (dd, J=8.8, 1.5 Hz, 2 H, H-7), 7.68 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 8.14 (d, J=8.8 Hz, 2 H, H-8), 8.23 (dd, J=8.4, 1.4 Hz, 2 H. ArH), 8.38 (s, 2 H, H-5), 8.55 (dd, J=7.2, 1.5 Hz, 2 H, ArH), 9.13 (s, 2 H, H-9), 10.78 (t, J=5.5 Hz, 2 H, CONH). Anal. (C₃₇ H₃₁ F₆ N₅ O₂.0.5H₂ O) C, H, N.

EXAMPLE 36 Preparation of Compound 32 of Table 1 by the Method of Scheme 2

Reaction of 2-amino-3,5-dimethylbenzoic acid and methyl iodobenzoate as reported (Rewcastle and Denny, Synth. Comm., 1987, 17, 309), and purification of the product on silica gel, eluting with EtOAc/petroleum ether (1:4), gave 3,5-dimethyl-2-[(2-methoxycarbonyl)phenylamino-benzoic acid, (73%), mp (EtOAc/petroleum ether) 210-211.5° C. ¹ H NMR (CDCl₃) δ 2.07 (s, 3 H, CH₃), 2.40 (s, 3 H, CH₃), 3.97 (s, 3 H, COOCH₃) 6.40 (dd, J=8.3, 0.9 Hz, 1 H, H-6'), 6.90-6.94 (m, 1 H, H-4'), 7.28-7.32 (m, 2 H, H-5' and H-4 or H-6), 8.00 (d, J=1.8 Hz, 1 H, H-6 or H-4), 8.03 (dd, J=8.0, 1.6 Hz, 1 H, H-3'), 9.45 (br s, 1 H, NH).

Reduction of this as above via the imidazolide gave methyl 2-[N-(4,6-dimethyl-2-hydroxymethyl)phenylamino]benzoate (86%), mp (EtOAc/petroleum ether) 105-106° C. ¹ H NMR (CDCl₃) δ 1.83 (br s, 1 H, OH), 2.13 (s, 3 H, CH₃), 2.36 (s, 3 H, CH₃), 3.92 (s, 3 H, COOCH₃), 4.51 (d, J=12.8 Hz, 1 H, CH₂ OH), 4.63 (d, J=12.8 Hz, 1 H, CH₂ OH), 6.22 (d, J=8.3 Hz, 1 H, H-3), 6.65 (br t, J=7.6 Hz, 1 H, H-5), 7.07 (br s, 1 H, H-3' or H-5'), 7.16 (br s, 1 H, H-5' or H-3'), 7.16-7.22 (m, 1 H, H-4), 7.95 (dd, J=8.0, 1.4 Hz, 1 H, H-6), 9.01 (br s, 1 H, NH).

Oxidation of this as above gave methyl 2-[N-(4,6-dimethyl-2-formyl)phenylamino]benzoate, (95%), mp (EtOAc/petroleum ether) 103-104° C. ¹ H NMR (CDCl₃) δ 2.19 (s, 3 H, CH₃), 2.40 (s, 3 H, CH₃), 3.95 (s, 3 H, COOCH₃), 6.31 (dd, J=8.3, 0.8 Hz, 1 H, H-3), 6.69-6.73 (m, 1 H, H-5), 7.20-7.24 (m, 1 H, H-4), 7.37 (d, J=1.6 Hz, 1 H, H-3' or H-5'), 7.60 (d, J=1.7 Hz, 1 H, H-5' or H-3'), 7.97 (dd, J=8.0, 1.6 Hz, 1 H, H-6), 9.42 (br s, 1 H, NH), 10.14 (s, 1 H, CHO).

Cyclisation of this as above gave crude methyl 5,7-dimethylacridine-4-carboxylate (99%). ¹ H NMR (CDCl₃) δ 2.53 (s, 3 H, CH₃), 2.88 (s, 3 H, CH₃), 4.12 (s, 3 H, COOCH₃), 7.49 (br s, 1 H, H-6 or H-8), 7.52 (dd, J=8.5, 7.0 Hz, 1 H, H-2), 7.57 (br s, 1 H, H-8 or H-6), 8.03 (dd, J=6.8, 1.4 Hz, 1 H, H-1 or H-3), 8.05 (dd, J=8.5, 1.4 Hz, 1 H, H-3 or H-1), 8.61 (s, 1 H, H-9). Hydrolysis of this as above gave 5,7-dimethylacridine-4-carboxylic acid (73%), mp (MeOH/TEA/AcOH) 312-315° C. ¹ H NMR [(CD₃)₂ SO/NaOD] d 2.49 [s, partially obscured by DMSO, 3 H, CH₃), 7.39-7.45 (m, 2 H, H-1 and H-2), 7.49 (br s, 1 H, H-6 or H-8), 7.67 (br s, 1H, H-8 or H-6), 7.85 (dd, J=7.7, 2.1 Hz, 1 H, H-3) and 8.76 (s, 1 H, H-9). Anal. (C₁₆ H₁₃ NO₂) C, H, N.

Activation and coupling of this as above gave bis[(5,7-dimethylacridine-4-carboxamido)-propyl]methylamine (32) as an orange oil (56%). ¹ H NMR (CDCl₃) δ 1.94-2.05 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.31 (s, 3 H, NCH₃), 2.45 (s, 6 H, 2×CH₃), 2.58 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 2.70 (s, 6 H, 2×CH₃), 3.68 (dd, J=7.2, 5.7 Hz, 4 H, 2×CHNH), 7.32 (br s, 2 H, H-6 or H-8) 7.41 (br s, 2 H, H-8 or H-6), 7.57 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 7.96 (dd, J=8.4, 1.4 Hz, 2 H, H-1), 8.49 (s, 2 H, H-9), 8.89 (dd, J=7.2, 1.5 Hz, 2 H, H-3) and 11.75 (br t, J=5.3 Hz, 2 H, 2×CONH). HRMS (FAB⁺) m/z calcd. for C₃₉ H₄₂ N₅ O₂ 612.3339 (MH⁺), found 612.3330. Anal. (C₃₉ H₄₁ N₅ O₂ 0.5H₂ O) C,H,N.

EXAMPLE 37 Preparation of Compound 20 of Table 1

The bis(6-fluoro)trihydrochloride (16) (0.52 g, 0.7 mmol) was heated with 40 aqueous dimethylamine (10 mL) in MeOH (10 mL) in a bomb at 100° C. for one week. Solvent and excess reagent was evaporated under reduced pressure, ammonia was added, and the mixture was extracted with CH₂ Cl₂. Evaporation and chromatography of the residue on alumina, eluting with a gradient of MeOH in CH₂ Cl₂, gave bis[(6-(dimethylamino)acridine-4-carboxamido)propyl]methylamine (20) (84%), mp (HCl salt from MeOH/EtOAc) 100° C. (dec). ¹ H NMR (free base in CDCl₃) δ 2.03 (quin, J=7.0 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.37 (s, 3 H, NCH₃), 2.82 (t, J=7.6 Hz, 4 H, 2×CH₂ NCH₃), 2.85 (s, 12 H, 2×N(CH₃)₂), 3.73 (q, J=6.1 Hz, 4 H, 2×CH₂ NH), 6.54 (d, J=2.2 Hz, 2 H, H-5), 6.67 (dd, J=9.2, 2.4 Hz, 2 H, H-7), 7.31 (d, J=9.2 Hz, 2 H, H-8), 7.40 (t, J=7.6 Hz, 2 H, H-2), 7.86 (dd, J=8.2, 1.6 Hz, 2 H, H-1), 8.21 (s, 2 H, H-9), 8.81 (dd, J=7.2, 1.6 Hz, 2 H, H-3), 12.15 (t, J=5.0 Hz, 2 H, 2×CONH).

EXAMPLE 38 Preparation of Compound 38 of Table 1

A suspension of phenazine-1-carboxylic acid [Rewcastle and Denny, Synth. Comm., 1987, 17, 1171] (1.30 g, 5.8 mmol) in DMF (8 mL) was treated with 1,1'-carbonyldiimidazole (1.13 g, 7.0 mmol), and the mixture was stirred at 45° C. for 30 min. After cooling, the mixture was diluted with CH₂ Cl₂ /petroleum ether (1:1) to complete precipitation of the crude imidazolide, which was collected, washed with petroleum ether and dried. The crude imidazolide (1.33 g, 4.85 mmol) was added to an ice-cold solution of N,N-bis(3-aminopropyl)methylamine (0.35 g, 2.41 mmol) in THF (15 mL), and the mixture was stirred at 20° C. for 4 h. Volatiles were removed under reduced pressure, and the residue was partitioned between CH₂ Cl₂ and aqueous Na₂ CO₃.

The organic layer was washed with water, dried and evaporated, and the residue was chromatographed on alumina-90. Elution with CH₂ Cl₂ /MeOH (20:1), followed by crystallization from EtOAc/iPr₂ O, gave bis[(phenazine-1-carboxamido)propyl]methylamine (38) (1.02 g, 63% from the acid), mp 153-154° C. ¹ H NMR [(CD₃)₂ SO] δ 1.87 (quin, J=6.5 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.27 (s, 3 H, CH₃), 2.62 (t, J=6.7 Hz, 4 H, 2×CH₂ NCH₃), 3.53 (q, J=5.7 Hz, 4 H, 2×CH₂ NH), 7.5-7.8 (m, 4 H, ArH), 7.8-8.1 (m, 6 H, ArH), 8.16 (d, J=8.6 Hz, 2 H, ArH), 8.47 (d, J=6.9 Hz, 2 H, ArH), 10.14 (t, J=5.0 Hz, 2 H, 2×NH). Treatment with MeOH/EtOAc/HCl (1 equiv.) gave the monohydrochloride salt, mp (MeOH/EtOAc) 233-235° C. Anal. (C₃₃ H₃₁ N₇ O₂.HCl.0.5H₂ O) C,H,N,Cl.

EXAMPLE 39 Preparation of Compound 39 of Table I

Activation and coupling of phenazine-2-carboxylic acid as above gave bis[(phenazine-2-carboxamido)propyl]methylamine (39), as a yellow solid (88%) mp 196-197.5° C. ¹ H NMR (CDCl₃) δ 1.90-1.96 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.34 (s, 3 H, NCH₃), 2.64 (t, J=6.2 Hz, 4 H, 2×CH₂ NCH₃), 3.71 (q, J=6.0 Hz, 2 H, 2×CH₂ NH), 7.66 (ddd, J=8.6, 6.6, 1.5 Hz, 2 H, H-7 or H-8), 7.72 (ddd, J=8.7, 6.6, 1.5 Hz, 2 H, H-8 or H-7), 7.99 (dd, J=8.7, 1.3 Hz, 2 H, H-6 or H-9), 8.12 (dd, J=8.4, 1.3 Hz, 2 H, H-9 or H-6), 8.16, (m, 4 H, H-4 and NH), 8.21 (dd, J=9.1, 1.9 Hz, 2H, H-3) and 8.44 (d, J=1.6 Hz, 2 H, H-1). Anal. (C₃₃ H₃₁ N₇ O₂) C,H,N HRMS (FAB⁺) M/z calcd for C₃₃ H₃₂ N₇ O₂ 558.2617 (MH⁺), found 558.2599.

EXAMPLE 40 Preparation of Compound 40 of Table I

Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 6-methylphenazine-1-carboxylic acid as above gave bis [(6-methylphenazine-1-carboxamido)propyl]methylamine (40) (47%), mp (HCl salt) 228-230° C. (MeOH/EtOAc). ¹ H NMR (CDCl₃) δ 2.06 (quin, J=6.9 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.39 (s, 3 H, N CH₃), 2.79 (s, 6 H, 2×ArCH₃), 2.81 (t, J=7.0 Hz, 4 H, 2×CH₂ NCH₃), 3.75 (q, J=6.1 Hz, 4 H, 2×CH₂ NH), 7.42 (t, J=7.8 Hz, 2 H, H-8), 7.61 (d, J=8.8 Hz, 2 H, 2×ArH), 7.87 (dd, J=8.5, 7.1 Hz, 4 H, H-3, 2×ArH), 8.27 (dd, J=8.7, 1.5 Hz, 2 H, H-4), 8.88 (dd, J=7.0, 1.5 Hz, 2 H, H-2), 10.93 (br s, 2 H, 2×CONH).

EXAMPLE 41 Preparation of Compound 41 of Table I

Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 6-chlorophenazine-1-carboxylic acid as above gave bis [(6-chlorophenazine-1-carboxamido)propyl]methylamine (41) (56%), mp (CH₂ Cl₂ /MeOH) 198-200° C. ¹ H NMR (CDCl₃) δ 2.01-2.06 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.37 (s, 3 H, NCH₃), 2.73 (t, J=7.2 Hz, 4 H, 2×CH₂ NCH₃), 3.72 (q, J=6.2 Hz, 2 H, 2×CH₂ NH), 7.62 (dd, J=8.7, 7.2 Hz, 2 H, H-8), 7.74 (dd, J=7.2, 1.2 Hz, 2 H, H-7 or H-9), 7.91 (dd, J=8.8, 1.2 Hz, 2 H, H-9 or H-7), 7.93 (dd, J=8.7, 7.1 Hz, 2 H, H-3), 8.39 (dd, J=8.7, 1.6 Hz, 2 H, H-4), 8.88 (dd, J=7.1, 1.6 Hz, 2 H, H-2), 10.59 (br t, J=5.1 Hz, 2H, 2×CONH), HRMS (FAB⁺) m/z calcd for C₃₃ H₂₉ Cl₂ N₇ O₄ 626.1838 (MH⁺), found 618.1840. Anal. (C₃₃ H₂₉ Cl₂ N₇ O₂) C, H, N, Cl).

EXAMPLE 42 Preparation of Compound 42 of Table I

Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 7-methylphenazine-1-carboxylic acid as above gave bis [(7-methylphenazine-1-carboxamido)propyl]methylamine (42) (63%), mp (HCl salt) 213-215° C. (MeOH/EtOAc). ¹ H NMR (CDCl₃) δ 2.06 (quin, J=6.9 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.44 (s, 6 H, 2×ArCH₃), 2.79 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.75 (q, J=6.2 Hz, 4 H, 2×CH₂ NH), 7.40 (dd, J=8.9, 1.6 Hz, 2 H, H-8), 7.62 (br s, 2 H, H-6), 7.77 (d, J=8.9 Hz, 2 H, H-9), 7.86 (dd, J=8.5, 7.1 Hz, 2 H, H-3), 8.22 (dd, J=8.6, 1.5 Hz, 2 H, H-4), 8.86 (dd, J=7.2, 1.5 Hz, 2 H, H-2), 10.85 (t, J=4.9 Hz, 2 H, 2×CONH). Anal. (C₃₅ H₃₅ N₇ O₂.HCl) C, H, N, Cl.

EXAMPLE 43 Preparation of Compound 43 of Table I

Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 7-methoxyphenazine-1-carboxylic acid as above gave bis[(7-methoxyphenazine-1-carboxamido)propyl]methylamine (43) (60%), mp (HCl salt) 225-229° C. (MeOH/EtOAc). ¹ H NMR (CDCl₃) δ 2.03 (quin, J=6.9 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.37 (s, 3 H, NCH₃), 2.74 (t, J=7.2 Hz, 4 H, 2×CH₂ NCH₃), 3.73 (q, J=6.3 Hz, 4 H, 2×CH₂ NH), 3.93 (s, 6 H, 2×ArOCH₃), 7.10 (d, J=2.7 Hz, 2 H, H-6), 7.28 (dd, J=9.1, 3.1 Hz, 2 H, 2×ArH), 7.78 (d, J=9.5 Hz, 2 H, H-9), 7.83 (dd, J=8.7, 1.5 Hz, 2 H, H-8), 8.17 (dd, J=8.6, 1.5 Hz, 2 H, 2×ArH), 8.81 (J=7.2, 1.5 Hz, 2 H, H-2), 10.77 (t, J=4.6 Hz, 2 H, 2×CONH). Anal. (C₃₅ H₃₅ N₇ O₄.2HCl.3H₂ O) C, H, N.

EXAMPLE 44 Preparation of Compound 44 of Table I

Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 7-chlorophenazine-1-carboxylic acid as above gave bis[(7-chlorophenazine-1-carboxamido)propyl]methylamine (44) (71%), mp (CH₂ Cl₂ /MeOH) 173-175° C. ¹ H NMR (CDCl₃) δ 1.99-2.06 (m, 4 H, CH₂ CH₂ CH₂), 2.37 (s, 3 H, NCH₃), 2.73 (t, J=7.2 Hz, 4 H, CH₂ NCH₃), 3.73 (q, J=6.5, 5.8 Hz, 2 H, CH₂ NH), 7.54 (dd, J=9.3, 2.4 Hz, 2 H, H-8), 7.84 (d, J=9.3 Hz, 2 H, H-9), 7.90 (d, J=2.5 Hz, 2 H, H-6), 7.92 (dd, J=8.7, 7.1 Hz, 2 H, H-3), 8.20 (dd, J=8.7, 1.6 Hz, 2 H, H-4), 8.88 (dd, J=7.1, 1.5 Hz, 2 H, H-2), 10.54 (br t, J=5.1 Hz, 2 H, 2×CONH). HRMS (FAB⁺) m/z calcd for C₃₃ H₂₉ Cl₂ N₇ O₄ 626.1838 (MH⁺), found 618.1844. Anal. (C₃₃ H₂₉ Cl₂ N₇ O₂) C, H, N, Cl.

EXAMPLE 45 Preparation of Compound 45 of Table I

Activation and coupling of the known [Rewcastle and Denny, Synth. Comm., 1987, 17, 1171] 8-methylphenazine-1-carboxylic acid as above gave bis [(8-methylphenazine-1-carboxamido)propyl]methylamine (45) (76%), mp (HCl salt) 215° C. (dec) (MeOH/EtOAc). ¹ H NMR (CDCl₃) δ 2.16 (quin, J=6.6 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.52 (s, 9 H, NCH₃, 2×ArCH₃), 2.93 (m, 4 H, 2×CH₂ NCH₃), 3.76 (q, J=6.3 Hz, 4 H, 2×CH₂ NH), 7.41 (d, J=8.6 Hz, 2 H, H-6), 7.77 (br s, 2 H, H-9), 7.86 (dd, J=8.5, 7.1 Hz, 4 H, H-3,7), 8.26 (dd, J=8.6, 1.5 Hz, 2 H, H-4), 8.87 (dd, J=7.7, 1.5 Hz, 2 H, H-2), 11.00 (br s, 2 H, 2×CONH).

EXAMPLE 46 Preparation of Compound 46 of Table I

Activation and coupling of the known [Rewcastle and Denny, Synth. Comm., 1987, 17, 1171] 8-methoxyphenazine-1-carboxylic acid as above gave bis[(8-methoxyphenazine-1-carboxamido)propyl]methylamine (46) (99%), mp 182-186° C. (dec.) (MeOH/EtOAc). ¹ H NMR (CDCl₃) δ 1.92 (m, 4 H, 2×CH₂), 2.30 (s, 3 H, NCH₃), 2.71 (m, 4 H, 2×CH₂), 3.60 (q, J=6.1 Hz, 4 H, 2×CH₂ NH), 3.85 (s, 6 H, 2×ArOCH₃), 7.06 (s, 2 H, H-9), 7.19 (dd, J=9.4, 2.4 Hz, 2 H, H-7), 7.69 (d, J=9.4 Hz, 2 H, H-6), 7.80 (dd, J=8.6, 7.2 Hz, 2 H, H-3), 8.11 (dd, J=8.5, 1.4 Hz, 2 H, H-4), 8.48 (J=7.1, 1.5 Hz, 2 H, H-2), 10.39 (t, J=5.4 Hz, 2 H, 2×CONH). Anal. (C₃₅ H₃₅ N₇ O₄) C, H, N.

EXAMPLE 47 Preparation of Compound 47 of Table I

Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 9-methylphenazine-1-carboxylic acid as above gave bis[(9-methylphenazine-1-carboxamido)propyl]methylamine (47) (82%), mp (HCl salt) 262-264° C. (MeOH/EtOAc). ¹ H NMR (CDCl₃) δ 1.99 (quin, J=7.3 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.32 (s, 3 H, NCH₃), 2.60 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 2.79 (s, 6 H, 2×ArCH₃), 3.75 (q, J=6.7 Hz, 4 H, 2×CH₂ NH), 7.56 (d, J=6.73 Hz, 2 H, H-8), 7.65 (dd, J=8.7, 7.2 Hz, 2 H, H-7), 7.89 (dd, J=8.7, 7.2 Hz, 2 H, H-3), 7.97 (d, J=8.6 Hz, 2 H, H-6), 8.27 (dd, J=8.7, 1.5 Hz, 2 H, H-4), 8.93 (dd, J=7.2, 1.5 Hz, 2 H, H-2), 10.94 (br s, 2 H, 2×CONH). Anal. (C₃₅ H₃₅ N₇ O₂ HCl) C, H, N, Cl.

EXAMPLE 48 Preparation of Compound 48 of Table I

Activation and coupling of 9-methylphenazine-1-carboxylic acid as above, and subsequent coupling with 1,4-bis(aminopropyl)piperazine gave a crude product, which was dissolved in MeOH/AcOH, treated with charcoal/Celite and filtered, then basified with Et₃ N to give bis[(9-methylphenazine-1-carboxamido)propyl]-1,4-piperazine (48) (45%) as the free base, mp (MeOH) 252-253° C. ¹ H NMR (hydrochloride salt in D₂ O) δ 2.07 (quin, J=7.5 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.89 (s, 6 H, 2×CH₃), 3.10 (t, J=7.0 Hz, 6 H, 3×CH₂), 3.29 (br s, 6 H, 3×CH₂), 3.64 (t, J=6.7 Hz, 6 H, 3×CH₂), 7.92-7.98 (m, 4 H, 4×ArH), 8.11 (dd, J=9.6, 7.2 Hz, 2 H, 2×ArH), 8.15 (d, J=8.4 Hz, 2 H, 2×ArH), 8.45 (dd, J=8.7, 1.3 Hz, 2 H, 2×ArH), 8.69 (dd, J=7.1, 1.3 Hz, 2 H, H-2). Anal. (C₃₈ H₄₀ N₈ O₂.0.5 H₂ O) C,H,N.

EXAMPLE 49 Preparation of Compound 49 of Table I

Activation and coupling of 9-methylphenazine-1-carboxylic acid as above, and subsequent coupling with ethylenetriamine gave a crude product, which was dissolved in MeOH/AcOH, treated with charcoal/Celite and filtered, then basified with Et₃ N to give bis[(9-methylphenazine-1-carboxamido)ethyl]-1,4-ethylenediamine (49) (33%) mp (HCl salt from MeOH/EtOAc) 281° C. (dec). ¹ H NMR (hydrochloride salt in D₂ O) δ 2.89 (s, 6 H, 2×CH₃), 3.38 (m, 8 H, 4×CH₂), 3.90 (q, J=6.9 Hz, 4 H, 2×CH₂), 7.90 (m, 4 H, 4×ArH), 8.07 (dd, J=8.6, 7.2 Hz, 2H, H-3), 8.13 (d, J=8.2 Hz, 2 H, 2×ArH), 8.44 (dd, J=8.7, 1.4 Hz, 2 H, 2×ArH), 8.71 (dd, J=7.1, 1.4 Hz, 2 H, H-2). Anal. HRMS (FAB⁺) m/z calcd for C₃₄ H₃₄ N₈ O₂ 586.61, found 587.29.

EXAMPLE 50 Preparation of Compound 50 of Table I

Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 9-methoxyphenazine-1-carboxylic acid as above gave bis[(9-methoxyphenazine-1-carboxamido)propyl]methylamine (50) (86%), mp (CH₂ Cl₂ /MeOH) 220-222° C. ¹ H NMR (CDCl₃) δ 1.99-2.05 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.39 (s, 3 H, NCH₃), 2.73 (t, J=7.6 Hz, 4 H, 2×CH₂ NCH₃), 3.66 (q, J=6.0 Hz, 2 H, 2×CH₂ NH), 3.90 (s, 6 H, OCH₃), 6.60 (dd, J=6.7, 1.9 Hz, 2 H, H-6 or H-8), 7.32-7.38 (m, 4 H, H-7 and H-8 or H-6), 7.84 (dd, J=8.7, 7.2 Hz, 2 H, H-3), 8.11 (dd, J=8.7, 1.5 Hz, 2 H, H-4), 8.83 (dd, J=7.1, 1.5 Hz, 2 H, H-2), 11.12 (br t, J=4.7 Hz, 2 H, NH). HRMS (FAB⁺) m/z calcd for C₃₅ H₃₅ N₇ O₄ 618.2829 (MH⁺), found 618.2847. Anal. (C₃₅ H₃₅ N₇ O₄) C, H, N.

EXAMPLE 51 Preparation of Compound 51 of Table I

Activation and coupling of the known [Atwell et al., Eur. Pat. Appl. EP 172,744, February 1986; Chem Abstr. 1986, 105, 97496p] 9-phenoxyphenazine-1-carboxylic acid as above gave bis[(9-phenoxyphenazine-1-carboxamido)propyl]methylamine (51) as an orange oil (51%). ¹ H NMR (CDCl₃) δ 1.69-1.73 (m, 4 H, 2×CH₂ CH₂ CH₂), 1.97 (s, 3 H, NCH₃), 2.31 (t, J=7.3 Hz, 4 H, 2×CH₂ NCH₃), 3.43 (q, J=6.4 Hz, 2 H, 2×CH₂ NH), 7.11-7.14 (m, 6 H, H-2', H-6' and H-6 or H-8), 7.18 (t, J=7.5 Hz, 2 H, H-4'), 7.39 (t, J=7.5 Hz, 4 H, H-3' and H-5'), 7.69 (dd, J=8.7, 7.6 Hz, 2 H, H-7), 7.89 (dd, J=8.7, 1.0 Hz, 2 H, H-3, H-8 or H-6), 8.26 (dd, J=8.7, 1.5 Hz, 2 H, 11-4), 8.90 (dd, J=7.1, 1.5 Hz, 2 H, H-2) and 10.98 (br t, J=5.2 Hz, 2 H, 2×CONH); HRMS (FAB⁺) m/z calcd for C₄₅ H₄₀ N₇ O₄ 742.3142 (MH⁺), found 742.3147.

EXAMPLE 52 Preparation of Compound 52 of Table I

Activation and coupling of the known [Rewcastle et al., Synth. Comm., 1987, 17, 1171] 9-fluorophenazine-1-carboxylic acid as above gave bis[(9-fluorophenazine-1-carboxamido)propyl]methylamine (52) (87%), mp (CH₂ Cl₂ /MeOH) 186-187° C. ¹ H NMR (CDCl₃) δ 2.00-2.04 (m, 4 H, CH₂ CH₂ CH₂), 2.36 (s, 3 H, NCH₃), 2.72 (t, J=7.4 Hz, 4 H, CH₂ NCH₃), 3.73 (q, J=6.2 Hz, 2 H, CH₂ NH), 7.30-7.35 (m, 2 H, H-7 or H-8), 7.54-7.60 (m, 2 H, H-8 or H-7), 7.84 (d, J=9.0 Hz, 2 H, H-6), 7.94 (dd, J=8.7, 7.0 Hz, 2 H, H-3), 8.25 (dd, J=8.7, 1.5 Hz, 2 H, H-4), 8.95 (dd, J=7.0, 1.5 Hz, 2 H, H-2), 10.94 (br t, J=5.0 Hz, 2 H, 2×CONH). HRMS (FAB⁺) m/z calcd for C₃₃ H₂₉ F₂ N₇ O₄ 594.2429 (MH⁺), found 594.2403. Anal. (C₃₃ H₂₉ F₂ N₇ O₂.0.5H₂ O) C, H, N.

EXAMPLE 53 Preparation of Compound 53 of Table I

Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 9-chlorophenazine-1-carboxylic acid as above gave bis[(9-chlorophenazine-1-carboxamido)propyl]methylamine (53) (86%), mp (CH₂ Cl₂ /MeOH) 169-171.5° C. ¹ H NMR (CDCl₃) δ 1.99-2.03 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.32 (s, 3 H, NCH₃), 2.62 (t, J=7.4 Hz, 4 H, 2×CH₂ NCH₃), 3.70 (q, J=6.2 Hz, 2 H, CH₂ NH), 7.64 (dd, J=8.8, 7.4 Hz, 2 H, H-7), 7.80 (dd, J=7.2, 1.0 Hz, 2 H, H-6 or H-8), 7.95 (dd, J=8.7, 7.2 Hz, 2 H, H-3), 8.01 (dd, J=8.7, 1.0 Hz, 2 H, H-8 or H-6), 8.27 (dd, J=8.7, 1.5 Hz, 2 H, H-4), 8.99 (dd, J=7.2, 1.5 Hz, 2 H, H-2), 10.94 (br t, J=5.0 Hz, 2 H, 2×CONH). HRMS (FAB⁺) m/z calcd for C₃₃ H₂₉ Cl₂ N₇ O₄ 626.1838 (MH⁺), found 618.1848. Anal. (C₃₃ H₂₉ Cl₂ N₇ O₂) C, H, N.

EXAMPLE 54 Preparation of Compound 54 of Table I

A solution of 9-fluorophenazine-1-carboxylic acid [Rewcastle et al., J. Synth Comm, 1987, 17, 1171] (200 mg, 0.8 mmol) in Me₂ NH (40% aqueous, 20 mL) was heated at 100° C. in a bomb for 3 h. The resulting intensely purple solution was diluted with water and then neutralized with AcOH. The aqueous solution was then extracted with CHCl₃ (3×50 mL) until all color was extracted. The organic layer was further washed with water (1×150 mL), then dried over Na₂ SO₄ and the solvent removed under reduced pressure. The resulting purple solid was dissolved in a minimal amount of CH₂ Cl₂, and peteoleum ether was added until crystallization occurred, giving 9-(dimethylamino)phenazine-1-carboxylic acid as dark purple needles (210 g, 95%), mp 186-187.5° C. ¹ H NMR (CDCl₃) δ 3.16 [s, 6 H, N(CH₃)₂ ], 7.26 (dd, J=6.8, 1.8 Hz, 1 H, H-6 or H-8), 7.81-7.88 (m, 2 H, H-7 and H-8 or H-6), 8.01 (dd, J=8.7, 7.0 Hz, 1 H, H-3), 8.48 (dd, J=8.7, 1.2 Hz, 1 H, H-4) and 8..91 (dd, J=7.0, 1.3 Hz, 1 H, H-2). Anal. (C₁₅ H₁₃ N₃ O₂) C, H, N. Activation and coupling of this as above gave bis[((9-dimethylamino)phenazine-1-carboxamido)propyl]methylamine (54) as a red-purple oil (78%). ¹ H NMR (CDCl₃) δ 1.91-2.00 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.29 (s, 3 H, NCH₃), 2.57 (t, J=7.3 Hz, 4 H, CH₂ NCH₃), 3.05 (s, 12 H, 2×N(CH₃)₂, 3.68 (q, J=6.5 Hz, 2 H, CH₂ NH), 7.07 (dd, J t 7.2, 1.3 Hz, 2 H, H-6 or H-8), 7.65 (dd, J=8.7, 7.3 Hz, 2 H, H-7), 7.70 (dd, J=8.7, 1.3 Hz, 2 H, H-8 or H-6), 7.90 (dd, J=8.6, 7.1 Hz, 2 H, H-3), 8.27 (dd, J=8.6, 1.4 Hz, 2 H, H-4), 8.87 (dd, J=7.1, 1.4 Hz, 2 H, H-2) and 10.99 (br t, J=5.1 Hz, 2 H, 2×CONH); HRMS (FAB⁺) m/z calcd for C₃₇ H₄₂ N₉ O₂ 644.3461 (MH⁺), found 644.3485.

EXAMPLE 55 Preparation of Compound 55 of Table 1

The bis(5-fluoro) analogue (11) was heated at 100° C. in excess 40% aqueous dimethylamine/MeOH for 8 weeks in a pressure vessel, the solvents were then removed by evaporation, and the residue was chromatographed on alumina to give bis[3-(5-(dimethylamino)acridine-4-carboxamido)propyl]methylamine (55) (60%) as a foam. ¹ H NMR (CDCl₃) δ 1.97 (quin, J=7.3 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.30 (s, 3 H, NCH₃), 2.59 (t, J=7.3 Hz, 4 H, CH₂ N(CH₃)CH₂), 3.01 (s, 12 H, 2×N(CH₃)₂), 3.68 (q, J=6.7 Hz, 4 H, 2×CH₂ NH), 7.12 (dd, J=7.2, 0.9 Hz, 2 H, H-6), 7.39 (dd, J=8.4, 7.3 Hz, 2 H, H-7), 7.51 (dd, J=8.2, 0.8 Hz, 2 H, H-8), 7.62 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 8.04 (dd, J=8.4, 1.4 Hz, 2 H, H-1), 8.70 (s, 2 H, H-9), 8.91 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.94 (br s, 2 H, 2×CONH). Anal. (C₃₉ H₄₃ N₇ O₂.H₂ O) C, H.

EXAMPLE 56 Preparation of Compound 56 of Table 1

The bis(7-fluoro) analogue (27) was heated at 100° C. in excess 40% aqueous dimethylamine/MeOH for 6 weeks in a pressure vessel, the solvents were then removed by evaporation, and the residue was chromatographed on alumina to give bis[3-(7-(dimethylamino)acridine-4-carboxamido)propyl]methylamine (56) (89%) as a foam. ¹ H NMR (CDCl₃) δ 2.08 (quin, J=7.0 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.40 (s, 3 H, NCH₃), 2.86 (t, J=7.6 Hz, 4 H, CH₂ N(CH₃)CH₂), 2.99 (s, 12 H, 2×N(CH₃)₂), 3.75 (q, J=6.1 Hz, 4 H, 2×CH₂ NH), 6.30 (d, J=2.8 Hz, 2 H, H-8), 7.18 (dd, J=9.5, 2.8 Hz, 2 H, H-6), 7.44 (dd, J=8.2, 7.2 Hz, 2 H, H-2), 7.67 (d, J=9.5 Hz, 2 H, H-5), 7.82 (dd, J=8.5, 1.4 Hz, 2 H, H-1), 8.13 (s, 2 H, H-9), 8.69 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.84 (t, J=5.0 Hz, 2 H, 2×CONH). Anal. (C₃₉ H₄₃ N₇ O₂.H₂ O) C, H, N.

EXAMPLE 57 Preparation of Compound 57 of Table 1 by the Method of Scheme 1

Reaction of 2,5-dimethylaniline and 2-iodoisophthalic acid under the conditions described in Example 1 gave crude N-(2,5-dimethyphenyl)isophthalic acid. This was cyclized directly with PPA to give 5,8-dimethylacridone-4-carboxylic acid (46% overall): mp (MeOH/H₂ O) 343-346° C.; ¹ H NMR [(CD₃)₂ SO] δ 2.87 (s, 6 H, 2×CH₃), 6.98 (d, J=7.3 Hz, 1 H, H-6), 7.33 (t, J=7.7 Hz, 1 H, H-2), 7.51 (d, J=7.5 Hz, 1 H, H-7), 8.41 (dd, J=7.6, 1.6 Hz, 1 H, H-1), 8.46 (dd, J=7.9, 1.6 Hz, 1 H, H-3), 12.00 (br s, 1 H, NH), 13.93 (br s, 1 H, COOH). Anal. (C₁₆ H₁₃ NO₃) C, H, N.

Reduction of 5,8-dimethylacridone-4-carboxylic acid as above gave 5,8-dimethylacridine-4-carboxylic acid (82%): mp (MeOH/H₂ O) 239-241° C.; ¹ H NMR [(CD₃)₂ SO] δ 2.78 (s, 3 H, CH₃), 2.83 (s, 3 H, CH₃), 7.50 (d, J=6.7 Hz, 1 H, H-6), 7.81 (d, J=7.0 Hz, 1 H, H-7), 7.88 (dd, J=8.3, 7.2 Hz, 1 H, H-2), 8.62 (dd, J=8.4, 1.4 Hz, 1 H, H-1), 8.76 (dd, J=7.0, 1.4 Hz, 1 H, H-3), 8.61 (s, 1 H, H-9) 17.48 (s, 1 H, COOH). Anal. (C₁₆ H₁₃ NO₂) C, H, N.

Activation and coupling of 5,8-dimethylacridine-4-carboxylic acid as above gave bis-[3-(5,8-dimethylacridine-4-carboxamido)propyl]methylamine (57) (79%), mp (CH₂ Cl₂ /hexane) 119-124° C. ¹ H NMR (CDCl₃) δ 2.00 (quin, J=7.3 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.31 (s, 3 H, NCH₃), 2.60 (t, J=7.4 Hz, 4 H, CH₂ N(CH₃)CH₂), 2.70 (s, 6 H, 2×CH₃), 2.73 (s, 6 H, 2×CH₃), 3.70 (q, J=6.7 Hz, 4 H, 2×CH₂ NH), 7.16 (d, J=7.1 Hz, 2 H, H-6), 7.40 (d, J=6.8 Hz, 2 H, H-7), 7.61 (dd, J=8.1, 7.3 Hz, 2 H, H-2), 8.06 (dd, J=8.3, 1.4 Hz, 2 H, H-1), 8.81 (s, 2 H, H-9), 8.93 (dd, J=7.1, 1.5 Hz, 2 H, H-3), 11.81 (br s, 2 H, 2×CONH). Anal. (C₃₉ H₄₁ N₅ O₂) C, H, N.

EXAMPLE 58 Preparation of Compound 58 of Table 1 by the Method of Scheme 1

Reaction of 3-methylanthranilic acid and 2-bromo-4-methylbenzoic acid under the conditions described in Example 1 gave crude N-(2-methyl-6-carboxyphenyl)-4-methylanthranilic acid. This was cyclized in PPA as above to give 1,5-dimethylacridone-4-carboxylic acid (49% overall), mp (MeOH) 317-318° C.; ¹ H NMR [(CD₃)₂ SO] δ 2.51 (s, 3 H, CH₃), 2.91 (s, 3 H, CH₃), 7.07 (d, J=8.1 Hz, 1 H, H-2), 7.20 (t, J=7.0 Hz, 1 H, H-7), 7.51 (d, J=7.0 Hz, 1 H, H-6), 8.05 (d, J=7.7 Hz, 1 H, H-3), 8.26 (d, J=7.8 Hz, 1 H, H-8), 12.45 (br s, 1 H, CO₂ H) Anal. (C₁₆ H₁₃ NO₃) C, H, N.

Reduction of 1,5-dimethylacridone-4-carboxylic acid as above gave 1,5-dimethylacridine-4-carboxylic acid (98%), mp (MeOH) 267° C. (dec.); ¹ H NMR [(CD₃)₂ SO] δ 2.83 (s, 3 H, CH₃), 2.93 (s, 3 H, CH₃), 7.70 (dd, J=8.1, 7.2 Hz, 2 H, H-2,7), 7.95 (d, J=6.7 Hz, 1 H, H-6), 8.25 (d, J=8.4 Hz, 1 H, H-8), 8.67 (d, J=7.3 Hz, 1 H, H-3 ), 9.63 (s, 1 H, H-9), 17.55 (s, 1 H, CO₂ H). Anal. (C₁₆ H₁₃ NO₂) C, H, N.

Activation and coupling of 1,5-dimethylacridine-4-carboxylic acid as above gave bis-[3-(1,5-dimethylacridine-4-carboxamido)propyl]methylamine (58) (82%), mp (CH₂ Cl₂ /hexane) 110-116° C. (dec.); ¹ H NMR (CDCl₃) δ 2.01 (quin, J=6.9 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.34 (s, 3 H, NCH₃), 2.64 (br t, 4 H, CH₂ N(CH₃)NCH₂), 2.77 (s, 12 H, 4×CH₃), 3.69 (q, J=6.7 Hz, 4 H, 2×CH₂ NH), 7.36 (dd, J=8.4, 6,9 Hz, 2 H, H-7), 7.42 (dd, J=7.2, 0.8 Hz, 2 H, H-6), 7.52 (d, J=6.8 Hz, 2 H, H-8), 7.75 (d, J=8.4 Hz, 2 H, H-2), 8.80 (s, 2 H, H-9), 8.8 (d, J=8.6 Hz, 2 H, H-3), 11.80 (br s, 2 H, 2×CONH). Anal. (C₃₉ H₄₁ N₅ O₂.2H₂ O) C, H, N.

EXAMPLE 59 Preparation of Compound 59 of Table 1 by the Method of Scheme 1

Reaction of 2-methyl-5-chloroaniline and 2-iodoisophthalic acid acid under the conditions described in Example 1 gave crude N-(2-methyl-5-chlorophenyl)isophthalic acid. This was cyclised directly with PPA to give 8-chloro-5-methylacridone-4-carboxylic acid (51% overall): mp (MeOH) 325-330° C.; ¹ H NMR [(CD₃)₂ O] δ 2.50 (s, 3 H, CH₃ ; overlapped with DMSO peak), 7.81 (d, J=7.2 Hz, 1 H, H-6), 7.38 (t, J=7.8 Hz, 1 H, H-2), 7.61 (d, J=7.7 Hz, 1 H, H-7), 8.43-8.48 (m, 2 H, H-1,3), 12.18 (br s, 1 H, NH), 14.10 (s, 1 H, CO₂ H). Anal. (C₁₅ H₁₀ ClNO₃) C, H, N.

Reduction of 8-chloro-5-methylacridone-4-carboxylic acid as above gave 8-chloro-5-methyl acridine-4-carboxylic acid (84%): mp (MeOH) 259-260° C.; ¹ H NMR [(CD₃)₂ SO] δ 2.81 (s, 3 H, CH₃), 7.86-7.95 (m, 3 H, H-1,2,3), 8.74 (d, J=8.4 Hz, 1 H, H-6), 8.80 (d, J=7.0 Hz, 1 H, H-7), 9.70 (s, 1 H, H-9), 16.83 (s, 1 H, CO₂ H). Anal. (C₁₅ H₁₀ ClNO₂) C, H, N.

Activation and coupling of 8-chloro-5-methyl acridine-4-carboxylic acid as above gave bis-[3-(8-chloro-5-methylacridine-4-carboxamido)propyl]methylamine (59) (81%): mp (CH₂ Cl₂ /hexane) 212-215° C.; ¹ H NMR (CDCl₃) δ 1.98 (quin, J=7.3 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.02 (s, 3 H, NCH₃), 2.60 (t, J=7.4 Hz, 4 H, CH₂ N (CH₃)CH₂), 2.67 (s, 6 H, 2×CH₃), 3.70 (q, 4 H, 2×CH₂ NH), 7.28 (dd, J=7.7, 0.9 Hz, 2 H, H-7), 7.32 (d, J=7.4 Hz, 2 H, H-6), 7.65 (dd, J=8.3, 7.2 Hz, 2 H, H-2), 8.07 (dd, J=8.6, 1.5 Hz, 2 H, H-1), 8.96 (dd, J=7.2, 1.5 Hz, 2 H, H-3), 9.01 (s, 2 H, H-9), 11.41 (t, J=5.3 Hz, 2 H, 2×CONH). Anal. (C₃₇ H₃₅ Cl₂ N₂ O₅.0.5H₂ O) C, H, N, Cl.

EXAMPLE 60 Preparation of Compound 60 of Table 1 by the Method of Scheme 2

A mixture of 3-methylanthranilic acid (7.6 g, 50 mmol), methyl-4-chloro-2-iodo benzoate (19.2 g, 65 mmol), Cu and CuI (catalytic) in 2,3 dibutanol (20 mL) was heated with benzene (30 mL) in an oil bath. After the benzene had distilled off, N-ethylmorpholine (50 mL) was added and the stirred mixture was heated at 110° C. for 18 h, then diluted with dilute HCl, extracted into EtOAc, and filtered to remove Cu salts. The organic layer was separated and extracted into dilute NH₄ OH, then the ammonium salt of the product precipitated. This was collected and stirred in dilute HCl, and the mixture was filtered and washed with water to give 2-[[(5-chloro-2-methoxycarbonyl)phenyl]amino]-3-methylbenzoic acid (6.6 g, 41%): mp (MeOH) 187-188.5° C.; ¹ H NMR [(CD₃)₂ SO] δ 2.10 (s, 3 H, CH₃), 3.87 (s, 3 H, OCH₃), 6.12 (d, J=2.0 Hz, 1 H, H-6'), 6.79 (dd, J=8.6, 2.0 Hz, 1 H, H-4'), 7.29 (t, J=7.6 Hz, 1 H, H-5), 7.52 (d, J=7.4 Hz, 1 H, H-4), 7.74 (d, J=7.4 Hz, 1 H, H-6), 7.89 (d, J=8.5 Hz, 1 H, H-3'), 9.90 (br s, 1 H, NH). Anal. (C₁₆ H₁₄ ClNO₄) C, H, N, Cl.

A solution of 2-[[(5-chloro-2-methoxycarbonyl)phenyl]amino]-3-methylbenzoic acid (6.0 g, 18.8 mmol) in dry THF (100 mL) was treated with CDI (6.0 g, 37.6 mmol) at 20° C. for 18 h, and the solution was then added dropwise to a suspension of NaBH₄ (0.69 g, 5 equiv.) in H₂ O (50 mL). When the reaction was complete (30 min, as monitored by TLC), the mixture was quenched with dilute HCl and extracted with CH₂ Cl₂. The filtered CH₂ Cl₂ layer was dried to give a crude product that was chromatographed on silica gel, eluting with a gradient of 1% MeOH in CH₂ Cl₂ to give methyl 4-chloro-2-[N-(2-hydroxymethyl-6-methyl)phenylamino]benzoate (1.0 g, 17%), mp (CH₂ Cl₂ /hexane) 114-115° C. ¹ H NMR (CDCl₃) δ 1.78 (br s, 1 H, OH), 2.18 (s, 3 H, CH₃), 3.92 (s, 3 H, CO₂ CH₃), 4.54 (dd, J=12.8, 4.3 Hz, 1 H, CHOH), 4.67 (dd, J=12.8, 4.3 Hz, 1 H, CHOH), 6.01 (d, J=2.0 Hz, 1 H, H-3), 6.63 (dd, J=8.3, 2.0 Hz, 1 H, H-5), 7.24-7.29 (m, 2 H, 2ArH), 7.35-7.39 (m, 1 H, ArH), 7.89 (d, J=8.6 Hz, 1 H, H-6), 9.22 (s, 1 H, NH). Anal. (C₁₆ H₁₆ ClNO₃) C, H, N.

A solution of methyl 4-chloro-2-[N-(2-hydroxymethyl-6-methyl)phenylamino]benzoate (0.72 g, 2.35 mmol) in EtOAc (100 mL) was heated under reflux for 7 h with MnO₂ (1 g). The mixture was filtered through celite to remove Mn residues, and the solvent was evaporated and the residue filtered through a column of silica gel in CH₂ Cl₂ to give methyl-4-chloro-2-[N-(2-formyl-6-methyl)phenylamino]benzoate (0.7 g, 98%): mp (MeOH/H₂ O) 81-82° C. ¹ H NMR (CDCl₃) δ 2.23 (s, 3 H, CH₃), 3.95 (s, 1 H, CO₂ CH₃), 6.27 (d, J=2.0 Hz, 1 H, H-3), 6.70 (dd, J=8.7, 2.0 Hz, 1 H, H-5), 7.37 (t, J=7.6 Hz, 1 H, H-4'), 7.58 (d, J=7.9 Hz, 1 H, H-5'), 7.81(dd, J=7.7, 1.3 Hz, 1 H, H-3¹), 7.92 (d, J=8.6 Hz, 1 H, H-6), 9.68 (br s, 1 H, NH), 10.15 (s, 1 H, CHO). Analysis for methyl-4-chloro-2-[N-(2-formyl-6-methyl)phenylamino]benzoate. Anal. (C₁₆ H₁₄ ClNO₃) C, H,N.

A solution of 4-chloro-2-[N-(2-formyl-6-methyl)phenylamino]benzoate (0.65 g, 2.1 mmol) in trifluoroacetic acid (8 mL) was stirred at 40° C. for 4 h under nitrogen. Excess reagent was removed under reduced pressure at 40° C., and the residue was suspended in 2 N NaOH (25 mL) and EtOH (18 mL) and heated for 1 h until a clear solution was obtained. The cooled reaction mixture was neutralized with AcOH, and the resulting precipitate was collected, washed with water and dried to give 1-chloro-5-methylacridine-4-carboxylic acid (0.56 g, 96%), mp (MeOH/H₂ O) 260° C. (dec.); ¹ H NMR (CDCl₃) δ 2.93 (s, 3 H, CH₃), 7.64 (dd, J=8.4, 7.9 Hz, 1 H, H-7), 7.83-7.86 (m, 2 H, H-2 & H-6 or H-8), 8.08 (d, J=8.6 Hz, 1 H, H-8 or H-6), 8.84 (d, J=7.8 Hz, 1 H, H-3), 9.4 (s, 1 H, H-9), 17.26 (s, 1 H, CO₂ H). Anal. (C₁₅ H₁₀ ClNO₂) C, H, N.

Activation and coupling of 1-chloro-5-methylacridine-4-carboxylic acid as above gave bis[3-(1-chloro-5-methylacridine-4-carboxamido)propyl]methylamine (60) (84%), mp (CH₂ Cl₂ /hexane) 156-158.5° C. ¹ H NMR (CDCl₃) δ 8 1.85 (quin, J=7.2 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.32 (s, 3 H, NCH₃), 2.60 (t, 4 H, CH₂ N(CH₃)CH₂), 2.74 (s, 6 H, 2×CH₃), 3.68 (q, J=6.7 Hz, 4 H, 2×CH₂ NH), 7.38 (dd, J=8.3, 6.8 Hz, 2 H, H-7), 7.52 (d, J=6.8 Hz, 2 H, H-6), 7.65 (d, L =8.0 Hz, 2 H, H-2),7.76 (d, J=8.5 Hz, 2 H, H-8), 8.80 (d, J=8.0 Hz, 2 H, H-3), 9.04 (s, 2 H, H-9), 11.50 (br s, 2 H, 2×CONH). Analysis for bis[3-(1-chloro-5-methylacridine-4-carboxamido)propyl]methylamine (60). Anal. (C₃₇ H₃₅ Cl₂ N₅ O₂) C, H, N, Cl.

EXAMPLE 61 Preparation of Compound 61 of Table 1

Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 3-methylphenazine-1-carboxylic acid gave bis[2-(3-methylphenazine-1-carboxamido)propyl]methylamine (61) as a yellow solid (84%), mp 75-78° C. (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 2.03 (quin, J=7.0 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.37 (s, 3 H, NCH₃), 2.67 (d, J=0.9 Hz, 6 H, 2×CH₃), 2.73 (t, J=7.2 Hz, 4 H, CH₂ N(CH₃)CH₂), 3.73 (q, J=6.3 Hz, 2 H, 2×CH₂ NH), 7.62-7.70 (m, 4 H, H-7 and H-8), 7.98-8.03 (m, 6 H, H-6, H-9 and H-2 or H-4), 8.73 (d, J=2.1 Hz, 2 H, H-2) and 10.88 (br t, J=5.2 Hz, 2 H, 2×CONH), HRMS (FAB⁺) m/z calcd for C₃₅ H₃₆ N₇ O₂ 586.2930 (MH⁺), found 586.2931. Anal. (C₃₅ H₃₅ N₇ O₂.H₂ O) C, H, N.

EXAMPLE 62 Preparation of Compound 62 of Table 1

Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 3-chlorophenazine-1-carboxylic acid gave bis[(3-chlorophenazine-1-carboxamido)propyl]methylamine (62) as a yellow solid (76%), mp 169-170° C. (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 2.02 (quin, J=6.9 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.36 (s, 3 H, NCH₃), 2.72 (t, J=7.3 Hz, 4 H, 2×CH₂ NCH₃), 3.71 (q, J=6.3 Hz, 2 H, 2×CH₂ NH), 7.69-7.76 (m, 4 H, H-7 and H-8), 7.94-8.00 (m, 4 H, H-6 and H-9), 8.20 (d, J=2.5 Hz, 2 H, H-4), 8.74 (d, J=2.5 Hz, 2 H, H-2) and 10.65 (br t, J=5.2 Hz, 2 H, 2×CONH), HRMS (FAB⁺) m/z calcd for C₃₃ H₂₉ ³⁵ Cl₂ N₇ O₂ 626.1838 (MH⁺), found 626.1824. Anal. C₃₃ H₂₉ Cl₂ N₇ O₂.H₂ O) C, H, N.

EXAMPLE 63 Preparation of Compound 63 of Table 1

Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 2-chlorophenazine-1-carboxylic acid gave bis[3-(2-chlorophenazine-1-carboxamido)propyl]methylamine (63) as a yellow solid (45%), mp 206-207° C. (CH₂ Cl₂ /n-hexane) ¹ H NMR (CDCl₃) δ 1.83 (quin, J=6.0 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.17 (s, 3 H, NCH₃), 2.72 (t, J=6.1 Hz, 4 H, CH₂ N(CH₃)CH₂), 3.67 (q, J=6.0 Hz, 2 H, 2×CH₂ NH), 7.03 (br t, J=5.9 Hz, 2 H, 2×CONH), 7.47 (d, J=9.4 Hz, 2 H, H-3 or H-4), 7.60-7.68 (m, 4 H, H-7 and H-8), 7.89 (d, J=9.3 Hz, 2 H, H-4 or H-3) 7.91-7.97 (m, 4 H, H-6 and H-9); HRMS (FAB⁺) m/z calcd for C₃₃ H₂₉ ³⁵ ClN₂ N₇ O₂ 626.1838 (MH⁺), found 626.1854. Anal. (C₃₃ H₂₉ Cl₂ N₇ O₂) C, H, N.

EXAMPLE 64 Preparation of Compound 64 of Table 1

Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 8-chlorophenazine-1-carboxylic acid gave bis[3-(8-chlorophenazine-1-carboxamido)propyl]methylamine (64) as a pale yellow solid, (85%), mp 210-212° C. (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 2.04 (quin, J=7.0 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.39 (s, 3 H, NCH₃), 2.73 (t, J=7.2 Hz, 4 H, CH2N(CH₃)CH₂), 3.74 (q, J=6.3 Hz, 4 H, 2×CH₂ NH), 7.56 (dd, J=9.2, 2.4 Hz, 2 H, H-7), 7.92 (dd, J=8.7, 7.2 Hz, 2 H, H-3), 7.98 (d, J=9.2, 2 H, H-6), 8.03 (d, J=2.2 Hz, 2 H, H-9), 8.26 (dd, J=8.7, 1.5 Hz, 2 H, H-4), 8.92 (dd, J=7.2, 1.5 Hz, 2 H, H-2) and 10.64 (br t, J=5.2 Hz, 2 H, 2×CONH); HRMS (FAB⁺) m/z calcd for C₃₃ H₃₀ ³⁵ Cl₂ N₇ O₂ 626.1838 (MH⁺), found 626.1860. Anal. (C₃₃ H₃₀ Cl₂ N₇ O₂) C, H, N, Cl.

EXAMPLE 65 Preparation of Compound 65 of Table I

Reaction of 2-bromo-3-nitrobenzoic acid and 2,5-xylidine gave 2-(2,5-dimethyl phenylamino)-3-nitro benzoic acid (65%): mp (benzene/acetone) 215-217° C. ¹ H NMR [(CD₃)₂ SO] δ 2.10 (s, 3 H, CH₃), 2.23 (s, 3 H, CH₃), 6.53 (s, 1H, H-6'), 6.79 (d, J=7.4 Hz, 1 H, H-4'), 7.02 (t, J=8.0 Hz, 1 H, H-5), 7.11 (d, J=7.7 Hz, 1 H, H-3'), 8.03 (dd, J=8.1, 1.4 Hz, 1 H, H-6), 8.22 (dd, J=7.7, 1.5 Hz, 1 H, H-4), 9.84 (br s, 1 H, NH), 13.8 (br s, 1 H, CO₂ H). Anal. (C₁₅ H₁₄ N₂ O₄) C, H, N.

Reductive ring closure of the above acid with NaOC₂ H₅ /NaBH₄ gave 6,9-dimethyl phenazine-1-carboxylic acid (64%), mp (MeOH) 246-247° C. ¹ H NMR [(CD₃)₂ SO] δ 2.78 (s, 3 H, CH₃), 2.83 (s, 3 H, CH₃), 7.80 (d, J=7.0 Hz, 1 H, H-7 or H-8), 7.84 (s, d, J=7.0 Hz, 1 H, H-7 or H-8), 8.12 (dd, J=8.5, 7.2 Hz, 1 H, H-3), 8.56 (d, J=8.7 Hz, 1 H, H-4), 8.66,(d, J=7.0 Hz, 1 H, H-2), 15.24 (br s, 1H, CO₂ H). Anal. (C₁₅ H₁₂ N₂ O₂). C, H, N.

Activation and coupling of the above acid gave bis[3-(6,9-dimethylphenazine-1-carboxamido) propyl]methylamine (65) as a bright yellow solid (53%), mp 97-101° C. (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 2.02 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.34 (s, 3 H, NCH₃), 2.60-2.68 (br m, 4 H, CH₂ N(CH₃)CH₂), 2.68 (s, 6 H, 2×ArCH₃), 2.78 (s, 6 H, 2×ArCH₃), 3.70 (q, J=6.6 Hz, 4 H, 2×CH₂ NH), 7.32-7.40 (m, 4 H, H-7 and H-8), 7.86 (dd, J=8.6, 7.2 Hz, 2 H, H-3), 8.28 (dd, J=8.7, 1.5 Hz, 2 H, H-4), 8.90 (dd, J=7.1, 1.5 Hz, 2 H, H-2) and 11.00 (br s, 2 H, 2×CONH); HRMS (FAB⁺) m/z calcd for C₃₇ H₄₀ N₇ O₂ 614.3243 (MH⁺), found 614.3237. Anal. (C₃₇ H₄₀ N₇ O₂.0.5H₂ O) C, H, N.

EXAMPLE 66 Preparation of Compound 66 of Table 1

A mixture of 5-chloro-2-methylaniline (8.63 g, 61.0 mmol), 2-bromo-3-nitrobenzoic acid (10.0 g, 41.0 mmol), CuCl (0.5 g), copper powder (0.1 g) in butane-2,3-diol (25 mL) and N-ethylmorpholine (15 mL) was stirred and heated for 18 h. at 70° C. The reaction mixture was diluted with 0.5 M NH₄ OH (500 mL), then filtered through Celite. The orange filtrate was then slowly added to a stirred solution of 2 N HCl and the resulting yellow precipitate was collected by filtration, dried and recrystallized to give 2-[(5-chloro-2-methyl)phenylamino]-3-benzoic acid as a bright yellow crystalline solid (70%), mp 228-230° C. (EtOAc/n-hexane). ¹ H NMR (CDCl₃) δ 2.35 (s, 3 H, CH₃), 6.79 (d, J=2.1 Hz, 1 H, H-6'), 6.96-7.00 (m, 2 H, H-4' and H-5'), 7.15 (d, J=8.0 Hz, 1 H, H-3'), 8.07 (dd, J=8.1, 1.8 Hz, 1 H, H-4 or H-6), 8.24 (dd, J=7.9, 1.7 Hz, 1 H, H-6 or H-4) and 9.51 (s, 1 H, COOH). Anal. (C₁₄ H₁₁ ClN₂ O₄) C, H, N.

A solution of 2-[(5-chloro-2-methyl)phenylamino]-3-benzoic acid (3.59 g, 11.7 mmol) and NaBH₄ (2.62 g, 68.8 mmol) in 2 M NaOH was heated at reflux for 8 h. The reaction mixture was then cooled and acidified with AcOH to precipitate the crude phenazine acid. This solid was collected and recrystallized to give 6-chloro-9-methylphenazine-1-carboxylic acid as mustard-yellow needles (45%), mp 255-257° C. (acetone). ¹ H NMR [(CD₃)₂ SO] δ 2.86 (s, 3 H, CH₃), 7.90 (dd, J=7.4, 1.1 Hz, 2 H, ArH), 8.11-8.18 (m, 2 H, ArH), 8.57-8.61 (m, 2 H, ArH) and 14.52 (br s, 1 H, COOH). Anal. (C₁₄ H₉ ClN₂ O₂) C, H, N, Cl.

The above 6-chloro-9-methylphenazine-1-carboxylic acid was activated and coupled to give bis[(6-chloro-9-methylphenazine-1-carboxamido)propyl]methylamine (66) as a green-yellow solid (84%), mp 200-202° C. (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 1.97 (quin, J=7.2 Hz, 4 H, 2×CH₂ CH₂ CH₂), 2.31 (s, 3 H, NCH₃), 2.59 (t, J=7.1 Hz, 4 H, CH₂ N(CH₃)CH₂), 2.76 (s, 6 H, 2×ArCH₃), 3.69 (q, J=6.7 Hz, 4 H, 2×CH₂ NH), 7.50 (dd, J=7.6, 1.0 Hz, 2 H, H-8), 7.78 (d, J=7.5 Hz, 2 H, H-7), 7.93 (dd, J=8.7, 7.2 Hz, 2 H, H-3), 8.41 (dd, J=8.7, 1.5 Hz, 2 H, H-2), 8.94 (dd, J=7.1, 1.5 Hz, 2 H, H-4), and 10.72 (br s, 2 H, 2×CONH); HRMS (FAB⁺) m/z calcd for C₃₅ H₃₄ ³⁵ Cl₂ N₇ O₂ 654.2151 (MH⁺), found 654.2159. Anal. (C₃₁ H₃₄ Cl₂ N₇ O₂.0.5H₂ O) C, H, N.)

EXAMPLE 67 Preparation of Compound 67 of Table 1

Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 4-methylphenazine-1-carboxylic acid gave bis[(4-methylphenazine-1-carboxamido)propyl]methylamine (67) as a bright yellow solid, (78%), mp 218-220° C. (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 2.04 (quin, J=7.0 Hz, 2 H, 2×CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.75 (t, J=7.3 Hz, 4 H, CH₂ N(CH₃)CH₂), 2.90 (s, 6 H, 2×CH₃)₁ 3.71 (q, J=6.3 Hz, 4 H, 2×CH₂ NH), 7.58 (ddd, J=8.6, 6.7, 1.3 Hz, 2 H, ArH), 7.65 (ddd, J=8.6, 6.6, 1.4 Hz, 2 H, ArH), 7.70 (dd, J=7.2, 1.0 Hz, 2 H, ArH), 7.94 (dd, J=8.6, 0.9 Hz, 2 H, ArH), 8.00 (d, J=8.7 Hz, 2 H, ArH), 8.77 (d, J=7.3 Hz, 2 H, ArH) and 10.88 (br s, 2 H, 2×CONH). HRMS (FAB⁺) m/z calcd for C₃₅ H₃₆ N₇ O₂ 586.2930 (MH⁺), found 586.2922. Anal. (C₃₅ H₃₆ N₇ O₂.2.5H₂ O) C, H, N.

EXAMPLE 68 Preparation of Compound 68 of Table 1

Activation of 9-methylphenazine-1-carboxylic acid and coupling with N,N'-bis(3-aminopropyl)ethylenediamine gave bis[3-(-9-methylphenazine-1-carboxamido)propyl]-1,2-ethylenediamine (68) as a gum, which was converted to the dihydrochloride salt (10%), mp (MeOH) 276° C. ¹ H NMR (D₂ O) δ 2.07 (quin, J=6.7 Hz, 4 H, 2×CH₂), 2.82 (s, 6 H, 2×ArCH₃), 3.17 (m, 4 H, 2×CH₂), 3.31 (br s, 4 H, 2×CH₂), 3.65 (t, J=6.6 Hz, 4 H, 2×CH₂), 7.87 (m, 4 H, 4×ArH), 7.96-8.00 (m, 4 H, 4×ArH), 8.27-8.30 (m, 2 H, 2×ArH), 8.60 (d, J=7.2 Hz, 2 H, 2×ArH). HRMS (FAB); Calculated for C₃₆ H₃₈ N₈ O₂ : 615.3196 Found: 615.3196.

EXAMPLE 69 Preparation of Compound 69 of Table 1

Activation of 6,9-dimethylphenazine-1-carboxylic acid and coupling with triethylenetetramine gave bis[2-(6-9-dimethylphenazine-1-carboxamido)ethyl]-1,2-ethylenediamine (69) (99%), mp (dihydrochloride salt from MeOH) 299° C. (dec.). ¹ H NMR (CF₃ CO₂ D) δ 3.06 (s, 6 H, 2×CH₃), 3.09 (s, 6 H, 2×CH₃), 3.87 (br s, 4 H, 2×CH₂), 3.91 (br s, 4 H, 2×CH₂), 4.27 (br s, 4 H, 2×CH₂), 8.20 (d, J=7.3 Hz, 2 H, H-7 or H-8), 8.24 (d, J=7.3 Hz, 2 H, H-7 or H-8), 8.43 (t, J=8.1 Hz, 2 H, H-3), 8.96 (d, J=8.8 Hz, 2 H, H-4), 9.02 (d, J=7.3 Hz, 2 H, H-2). Anal. (C₃₆ H₄₀ Cl₂ N₈ O₂) C, H, N.

EXAMPLE 70 Preparation of Compound 70 of Table 1

Activation of 9-methylphenazine-1-carboxylic acid and coupling with N,N'-bis(3-aminopropyl)butanediamine gave bis[2-(-9-methylphenazine-1-carboxamido)propyl]-1,4-butanediamine (70) (73%), mp (CH₂ Cl₂ /hexane) 86-90.5° C. ¹ H NMR (CDCl₃) 8 1.53 (quin, J=3.2 Hz, 4 H, 2×CH₂), 1.97 (quin, J=7.0 Hz, 4 H, CH₂), 2.62 (t, J=6.2 Hz, 4 H, 2×CH₂), 2.79 (t, J=7.0 Hz, 4 H, 2×CH₂), 2.88 (s, 6 H, 2×CH₃), 3.74 (q, J=6.6 Hz, 4 H, 2×CH₂), 7.71-7.78 (m, 4 H, ArH), 7.93 (dd, J=8.7, 7.2 Hz, 2 H, H-3), 8.08 (d, J=7.9, 0.8 Hz, 2 H, ArH), 8.34 (dd, J=8.7, 1.5 Hz, 2 H, H-4), 8.96 (dd, J=7.1, 1.5 Hz, 2 H, H-2), 11.05 (t, J=5.2 Hz, 2 H, 2×CONH). Anal. (C₃₈ H₄₂ N₈ O₂.1.5H₂ O) C, H, N.

EXAMPLE 71 Preparation of Compound 71 of Table 1

Activation of 5-methylacridine-4-carboxylic acid and coupling with triethylenetetramine gave bis[3-(5-methyl-acridine-4-carboxamido)ethyl]-1,2-ethylenediamine (71) (76%), mp (CH₂ Cl₂ /hexane) 167-170° C. ¹ H NMR (CDCl₃) δ 2.08 (s, 6 H, 2×CH₃), 2.85 (s, 4 H, 2×CH₂), 2.99 (t, J=6.2 Hz, 4 H, 2×CH₂), 3.74 (q, J=6.1 Hz, 4 H, 2×CH₂), 7.39 (dd, J=8.4, 6.8 Hz, 2 H, H-2), 7.57-7.61 (m, 4 H, H-6 & H-7), 7.75 (d, J=8.7 Hz, 2 H, H-8), 8.02 (dd, J=8.4, 1.5 Hz, 2 H, H-1), 8.68 (s, 2 H, H-9), 8.91 (dd, J=7.2, 1.5 Hz, 2 H, H-3), 11.81 (t, J=5.5 Hz, 2 H, 2×CONH). Anal. (C₃₆ H₃₆ N₆ O₂) C, H, N.

EXAMPLE 72 Preparation of Compound 72 of Table 1

Activation of acridine-4-carboxylic acid and coupling with triethylenetetramine gave bis[3-(acridine-4-carboxamido)ethyl]-1,2-ethylenediamine (72) (72%), mp (CH₂ Cl₂ /hexane) 170-171° C. ¹ H NMR (CDCl₃) 6 2.91 (s, 8 H, 4×CH₂), 3.53 (q, J=5.4 Hz, 4 H, 2×CH₂), 7.53 (t, J=7.4 Hz, 2 H, ArH), 7.68 (dd, J=8.3, 7.1 Hz, 2 H, ArH), 7.81-7.85 (m, 2 H, ArH), 8.03 (d, J=8.3 Hz, 2 H, ArH), 8.22 (d, J=8.9 Hz, 2 H, ArH), 8.26 (dd, J=8.5, 1.4 Hz, 2 H, ArH), 8.64 (dd, J=7.1, 1.6 Hz, 2 H, H-3), 9.87 (s, 2 H, H-9), 11.56 (t, J=5.0 Hz, 2 H, 2×CONH). Anal (C₃₄ H₃₂ N₆ O₂.2H₂ O) C, H, N.

EXAMPLE 73 Preparation of Compound 73 of Table 1

Activation of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 9-methylphenazine-1-carboxylic acid and subsequent coupling with N,N'-bis(2-aminoethyl)-1,3-propanediamine gave bis[(9-methylphenazine-1-carboxamido)ethyl]-1,3-propanediamine (73) as a yellow solid (68%), mp 194-195° C. (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 1.73 (quin, J=6.9 Hz, 2 H, CH₂ CH₂ CH₂), 2.79 (t, J=6.9 Hz, 4 H, 2×CH₂), 2.88 (s, 6 H, 2×ArCH₃), 2.97 (t, J=6.2 Hz, 4 H, 2×CH₂), 3.75 (q, J=6.0 Hz, 4 H, 2×CH₂), 7.64-7.69 (m, 2 H, ArH), 7.72 (dd, J=8.6, 6.8 Hz, 2 H, ArH), 7.93 (dd, J=8.7, 7.2 Hz, 2 H, ArH), 8.04 (dd, J=8.7, 0.9 Hz, 2 H, ArH), 8.33 (dd, J=8.7, 1.5 Hz, 2 H, ArH), 8.96 (dd, J=7.2, 1.5 Hz, 2 H, ArH) and 11.06 (br t, J=5.3 Hz, 2 H, 2×CONH); HRMS (FAB⁺) m/z calcd for C₃₅ H₃₇ N₈ O₂ 601.3039 (MH⁺), found 601.3043. Anal. (C₃₅ H₃₆ N₈ O₂.0.5H₂ O) C, H. N.

EXAMPLE 74 Preparation of Compound 74 of Table 1

Activation of 6-chloro-9-methylphenazine-1-carboxylic acid as above, and subsequent coupling with triethylenetetramine gave bis[2-(6-chloro-9-methylphenazine-1-carboxamido)ethyl]-1,2-ethylenediamine (74) as a yellow solid, 6%, mp 301° C. (dec.) (HCl salt) (MeOH/EtOAc). ¹ H NMR (CF₃ CO₂ D) δ 3.87 (br s, 4 H, 2×CH₂ NH), 4.04 (br s, 4 H, 2×CH₂ NH), 4.09 (s, 6 H, 2×CH₃), 4.29 (br s, 4 H, 2×CONHCH₂), 8.25 (br d, J=7.9 Hz, 2 H. ArH), 8.44 (br d, J=7.7 Hz, 2 H, ArH), 8.53 (br s, 2 H, ArH), 9.03 (br d, J=8.7 Hz, 2 H, ArH) and 9.09 (br s, 2 H. ArH); HRMS (FAB⁺) m/z calcd for C₃₄ H₃₃ ³⁵ Cl₂ N₈ O₂ 655.2104 (MH⁺), found 655.2075.

EXAMPLE 74a Preparation of Compound 74a of Table 1

N,N'-Dimethyl-N,N'-bis(cyanomethyl)ethylenediamine was synthesized by a reported method [Alcock et al., J. Chem Soc. Dalton Trans. 1987, 2643]. This compound (5.0 g, 100 mmol) was then hydrogenated over Raney nickel in absolute EtOH saturated with dry ammonia for 5 days at 20° C. (additional Raney nickel was added as required). The catalyst was removed by filtration through a pad of Celite, and evaporation of solvents gave essentially pure N,N'-dimethyl-N,N'-bis(2-aminoethyl)ethylenediamine (4.6 g, 88%). ¹ H NMR (CDCl₃) δ 2.24 (s, 6 H, 2×CH₃), 2.43 (br s, 4 H, 2×CH₂), 2.49 (s, 2 H, 2×CH₂) 2.73 (br s, 2 H, 2×CH₂), that was used directly. 9-Methyl phenazine-1-carboxylic acid (1.0 g, 4.2 mmol), and CDI (1.36 g, 8.4 mmol) in DMF (10 mL) was stirred at 50-60° C. for 1 h, then cooled to 20° C. Dry benzene (20 mL) and Sephadex LH-20 (2 g) was added, and the mixture was stirred at 20° C. for 1 h, then filtered through a pad of Celite to remove the Sephadex. The filtrate was evaporated to dryness under reduced pressure, and the residue was dissolved in dry THF (15 mL) and cooled in ice/salt. N,N'-Dimethyl-N,N' bis(2-aminoethyl)ethylenediamine (0.36 g, 2.1 mmol) was added, and the mixture was stirred while allowing it to warm to 20° C. Water (50 mL) was added, and and the THF was evaporated evaporated under reduced pressure. The resulting precipitate was filtered and washed with aq Na₂ CO₃ (3×50 mL) and water, then dissolved in CH₂ Cl₂ (100 mL) and dried (Na₂ SO₄). Evaporation of solvents gave a crude product that was chromatographed on silica gel, eluting with a gradient of 1-6% MeOH in CH₂ Cl₂) to give 74a as an oil (1.1 g, 78%). ¹ H NMR (CDCl₃) ₋₋ 2.33 (s, 6 H, 2×NCH₃), 2.63 (br s, 4 H, CH₃ NCH₂ CH₂ NCH₃), 2.74 (t, J=6.5 Hz, 4 H, CONHCH₂ CH₂), 2.83 (s, 6 H, 2×ArCH₃), 3.73 (q, J=6.2 Hz, 4 H, 2×CONHCH₂), 7.61 (d, J=6.7 Hz, 2 H, H-8), 7.68 (dd, J=8.7, 6.8 Hz, 2 H, H-7), 7.89 (dd, J=8.7, 7.2 Hz, 2 H, H-3), 7.98 (d, J=8.7 Hz, 2 H, H-6), 8.26 (dd, J=8., 1.5 Hz, 2 H, H-4), 8.89 (dd, J=7.0, 1.5 Hz, 2 H, H-2), 10.85 (t, J=5.2 Hz, 2 H, 2×CONH).

EXAMPLE 75 Preparation of Compound 75 of Table 1

N-(tert-butoxycarbonyl)-3,3'-diamino-N-methyldipropylamine was prepared as reported [Huang, T. L., Dredar, S. A., Manneh, V. A., Blankenship, J. W., Fries, D. S., J. Med. Chem., 1992, 35, 2414-24181. A solution of di-tert-butyldicarbonate (2.51 g, 11.5 mmol) in THF (15 mL) was added, over the course of 1.5 h., to a solution of 3,3'-diamino-N-methyldipropylamine (5.00 g, 34.4 mmol) in THF (15 mL), which was maintained at 0° C. (ice/water). The reaction mixture was stirred for a further 18 h at room temperature, then the solvent removed under reduced pressure and the resulting residue partitioned between NaCl (sat.) (100 mL) and CH₂ Cl₂ (200 mL). The CH₂ Cl₂ layer was washed with a further portion of NaCl solution (100 mL), then dried (Na₂ SO₄), and the solvent removed under reduced pressure to give N-(tert-butoxycarbonyl)-3,3'-diamino-N-methyldipropylamine (2.58 g, 46%) as a clear, viscous oil. ¹ H NMR (CDCl₃) δ 1.44 [br s, 9 H, C(CH₃)₃ ], 1.58-1.67 (m, 6 H, 2×CH₂ CH₂ CH₂ and NH₂), 2.22 (s, 3 H, NCH₃), 2.34-2.40 (m, 4 H, 2×CH₂ NCH₃), 2.74 (t, J=6.9 Hz, 2 H, CH₂ NH₂), 3.12-3.21 (br m, 2 H, CH₂ NHBOC) and 5.37 (br s, 1 H, NHBOC).

Phenazine-1-carboxylic acid (494 mg, 2.24 mmol) was prepared according to the literature method [Rewcastle, G. W., Denny, W. A., Baguley, B. C., J. Med. Chem., 1987, 30, 843-857], and subsequently reacted with CDI (544 mg, 3.36 mmol) in dry DMF (15 mL) for 2.5 h. at 30° C. The DMF was removed under reduced pressure and the resulting yellow solid was dissolved in a mixture of petroleum ether and CH₂ Cl₂ (40 mL, 3:1). Upon cooling, the imidazolide crystallized out and this crude material was used in the following coupling reaction. The crude imidazolide was suspended in THF (20 mL), cooled to 0° C. (ice/water), then a THF (20 mL) solution of the above N-(tert-butoxycarbonyl)-3,3'-diamino-N-methyldipropylamine (659 mg, 2.69 mmol) was added. The reaction mixture was allowed to stir for a further 2 h. at 0° C., then the solvent removed under reduced pressure and the resulting yellow oil partitioned between CH₂ Cl₂ (200 mL) and 1 M (Na₂ CO₃) (200 mL). The CH₂ Cl₂ layer was dried with Na₂ SO₄, the solvent removed under reduced pressure, and the resulting yellow-green oil was purified by chromatography on alumina (0.25% MeOH in CH₂ Cl₂) to give N-1-(3-{N-methyl-N-[N-(tert-butoxycarbonyl)-3-aminopropyl]}aminopropyl)phenazine-1-carboxamide (992 mg, 98%) as a yellow-green oil, which was used directly. ¹ H NMR (CDCl₃) δ 1.41 (br s, 9 H, C(CH₃)₃), 1.44 (br s, 2 H, CH₂ CH₂ CH₂ NHBOC), 1.95-2.04 (m, 2 H, CH₂ CH₂ CH₂ NHCOAr), 2.18 (s, 3 H, NCH₃), 2.46 (t, J=6.7 Hz, 2 H, CH₂ CH₂ CH₂ NHBOC), 2.56 (t, J=7.2 Hz, 2 H, CH₂ CH₂ CH₂ NHCOAr), 3.20 (m, 2 H, CH₂ NHBOC), 3.74 (q, J=6.2 Hz, 2 H, CH₂ NHCOAr), 5.45 (br s, 1 H, NHBOC), 7.89-8.00 (m, 3 H, ArH), 8.22-8.26 (m, 1 H, ArH), 8.28-8.32 (m, 1 H, ArH), 8.40 (dd, J=8.7, 1.5 Hz, 1 H, ArH), 9.02 (dd, J=7.1, 1.5 Hz, 1 H, ArH) and 11.03 (br s, 1 H, CONH).

To a solution of the above BOC-protected amine (545 mg, 1.21 mmol) in CH₂ Cl₂ (8 mL), was added trifluoroacetic acid (8 mL). This mixture was stirred at room temperature for 2 h. at which point the reaction was complete by TLC. All solvents were removed under reduced pressure and the oily residue partitioned between CH₂ Cl₂ (100 mL) and 1 M (Na₂ CO₃) (100 mL). The aqueous layer was extracted with additional CH₂ Cl₂ (4×100 mL) and all CH₂ Cl₂ extracts were combined and dried with Na₂ SO₄. The solvent was removed under reduced pressure to give N-1-{3-[N-methyl-N-(3-aminopropyl)]aminopropyl}phenazine-1-carboxamide (392 mg, 92%) as a green-yellow oil, which was used directly. ¹ H NMR (CDCl₃) δ 1.61-1.67 (m, 4 H, CH₂ CH₂ CH₂ NH₂), 2.00 (quin, J=7.1 Hz, 2 H, CH₂ CH₂ CH₂ NHCOAr), 2.29 (s, 3 H, NCH₃), 2.46 (t, J=7.2 Hz, 2 H, CH₂ CH₂ CH₂ NH₂), 2.59 (t, J=7.2 Hz, 2 H, CH₂ CH₂ CH₂ NHCOAr), 2.75 (t, J=6.8 Hz, 2 H, CH₂ NH₂), 3.72 (q, J=6.5 Hz, 2 H, CH₂ NHCOAr), 7.89-7.99 (m, 3 H, ArH), 8.22-8.25 (m, 1 H, ArH), 8.28-8.32 (m, 1 H, ArH), 8.40 (dd, J=8.6, 1.5 Hz, 1 H, ArH), 9.01 (dd, J=7.1, 1.5 Hz, 1 H, ArH) and 11.01 (br s, 1 H, CONH).

The known [Atwell, G. J., Rewcastle, G. W., Baguley, B. C., Denny, W. A., J. Med. Chem., 1987, 30, 664-669] acridine-4-carboxylic acid (274 mg, 1.23 mmol) was reacted with CDI (300 mg, 1.85 mmol) to form the imidazolide which was isolated as above. The imidazolide was suspended in THF (15 mL), the suspension cooled to 0° C. (ice/water), then a solution of the above amine (392 mg, 1.12 mmol) in THF (10 mL) slowly added. The reaction mixture was stirred for 2 h at 0° C., then 18 h. at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between CH₂ Cl₂ (100 mL) and 1 M (Na₂ CO₃) (100 mL). The CH₂ Cl₂ layer was dried with Na₂ SO₄, the solvent removed under reduced pressure to give an orange solid which was purified by chromatography on alumina (0.5% MeOH in CH₂ Cl₂ as eluant) and silica (1% MeOH and 0.25% triethylamine in CH₂ Cl₂ as eluant) to give N-1-{3-[{3-[(acridinyl-4-carbonyl)amino]propyl}(methyl)amino]propyl}phenazine-1-carboxamide (75) (as a pale yellow solid; mp 171-173° C. (CH₂ Cl₂ /n-hexane), ¹ H NMR (CDCl₃) δ 1.88 (quin, J=5.6 Hz, 2 H, CH₂ CH₂ CH₂), 2.02 (quin, J=6.0 Hz, CH₂ CH₂ CH₂), 2.38 (s, 3 H, NCH₃), 2.65-2.70 (m, 4 H, 2×CH₂ NCH₃), 3.62-3.68 (m, 2 H, CH₂ NHCO), 3.76 (q, J=6.5 Hz, 2 H, CH₂ NHCO), 7.11 (t, J=7.7 Hz, 1 H, ArH), 7.22-7.29 (m, 1 H, ArH), 7.36 (d, J=8.3 Hz, 1 H, ArH), 7.65 (ddd, J=8.3, 6.9, 1.5 Hz, 1 H, ArH), 7.85-7.93 (m, 3 H, ArH), 8.00 (dd, J=7.5, 0.9 Hz, 1 H, ArH), 8.09-8.13 (m, 1 H, ArH), 8.23-8.27 (m, 1 H, ArH), 8.36 (dd, J=8.6, 1.5 Hz, 1 H, ArH), 8.42 (d, J=8.1 Hz, 1 H, ArH), 8.53 (dd, J=8.0, 1.2 Hz, 1 H, ArH), 8.88 (dd, J=7.2, 1.5 Hz, 1 H, ArH), 9.15 (s, 1 H, H-9), 11.03 [br s, 1 H, NH (phenazine)] and 12.55 [br s, 1 H, NH (acridine)]). Anal. (C₃₄ H₃₂ N₆ O₂.2H₂ O) C, H, N.

EXAMPLE 76 Preparation of Compound 76 of Table 1 by the Method of Scheme 3

Activation and coupling of 9-methylphenazine-1-carboxylic acid [Rewcastle, G. W., Denny, W. A., Baguley, B. C., J. Med. Chem., 1987, 30, 843-857] with N-(tert-butoxycarbonyl)-3,3'-diamino-N-methyldipropylamine as in Example 75 gave N-1-(3-{(N-methyl-N-[N-(tert-butoxycarbonyl)-3-aminopropyl]}aminopropyl)-9-methylphenazine-1-carboxamide as a yellow-green oil (89%), which was used directly. ¹ H NMR (CDCl₃) δ 1.41 (br s, 9 H, C(CH₃)₃), 1.65 (quin, J=6.6 Hz, 2 H, CH₂ CH₂ CH₂ NHBOC), 1.98 (quin, J=7.2 Hz, 2 H, CH₂ CH₂ CH₂ NHCOAr) 2.24 (s, 3 H, NCH₃), 2.42 (t, J=6.7 Hz, 2 H, CH₂ CH₂ CH₂ NHBOC), 2.53 (t, J=7.3 Hz, 2 H, CH₂ CH₂ CH₂ NHCOAr) 2.94 (s, 3 H, ArCH₃), 3.12-3.23 (br s, 2 H, CH₂ NHBOC), 3.73 (q, J=6.7 Hz, 2 H, CH₂ NHCOAr), 5.39 (br s, 1 H, NHBOC), 7.77 (dt, J=6.5, 1.1 Hz, 1 H, ArH), 7.81 (dd, J=8.5, 6.8 Hz, 1 H, ArH), 7.97 (dd, J=8.7, 7.2 Hz, 1 H, ArH), 8.14 (d, J=8.4 Hz, 1 H, ArH), 8.39 (dd, J=8.6, 1.5 Hz, 1 H, ArH), 9.02 (dd, J=7.2, 1.5 Hz, 1 H, ArH) and 11.13 (br t, J=5.2 Hz, 1 H, CONH).

Deprotection of the above BOC-protected amine as in Example 75 gave N-{-3-[N-methyl-N-(3-aminopropyl)]aminopropyl}-9-methylphenazine-1-carboxamide as a green-yellow oil, (85%), which was used directly. ¹ H NMR (CDCl₃) δ 1.62 (quin, J=7.0 Hz, 2 H, CH₂ CH₂ CH₂ NH₂), 1.98 (quin, J=7.3 Hz, 2 H, CH₂ CH₂ CH₂ NHCOAr), 2.26 (s, 3 H, NCH₃), 2.43 (t, J=7.2 Hz, 2 H, CH₂ CH₂ CH₂ NH₂), 2.53 (t, J=7.3 Hz, 2 H, CH₂ CH₂ CH₂ NHCOAr), 2.75 (m, 2 H, CH₂ NH₂), 2.93 (s, 3 H, ArCH₃), 3.73 (q, J=6.7 Hz, 2 H, CH₂ NHCOAr), 7.76 (dt, J=6.7, 1.3 Hz, 1 H, ArH)N, 7.81 (dd, J=8.4, 6.9 Hz, 1 H, ArH), 7.97 (dd, J=8.6, 7.1 Hz, 1 H, ArH), 8.13 (dd, J=8.7, 1.0 Hz, 1 H, ArH), 8.38 (dd, J=8.7, 1.5 Hz, 1 H, ArH), 9.00 (dd, J=7.1, 1.5 Hz, 1 H, ArH) and 11.11 (br s, 1 H, CONH).

Activation and coupling of 5-methylacridine-4-carboxylic acid [Atwell, G. J., Rewcastle, G. W., Baguley, B. C., Denny, W. A., J. Med. Chem., 1987, 30, 664-669] with the above deprotected amine as in Example 75 gave N-1-{3-[{3-[(5-methylacridinyl-4-carbonyl)amino]propyl}(methyl)amino]propyl}-9-methylphenazine-1-carboxamide (76) as a pale yellow solid (66%), mp 116-121° C. (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 1.94-2.02 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.32 (s, 3 H, NCH₃), 2.58-2.63 (m, 4 H, 2×CH₂ NCH₃), 2.73 (s, 3 H, ArCH₃), 2.80 (s, 3 H, ArCH₃), 3.66-3.74 (m, 4 H, 2×CH₂ NHCO), 7.31 (dd, J=8.4, 6.8 Hz, 1 H, ArH), 7.52 (m, 2 H, ArH), 7.59 (dd, J=8.2, 7.2 Hz, 1 H, ArH), 7.63-7.69 (m, 2 H, ArH), 7.90 (dd, J=8.7, 7.2 Hz, 1 H, ArH), 7.95-8.00 (m, 2 H, ArH), 8.28 (dd, J=8.7, 1.5 Hz, 1 H, ArH), 8.61 (s, 1 H, H-9), 8.90-8.95 (m, 2 H, ArH), 10.87 [br s, 1 H, NH (phenazine)] and 11.78 [br s, 1 H, NH (acridine)]. Analysis for N-1-{3-[{3-[(5-methylacridinyl-4-carbonyl)amino]propyl}(methyl)amino]propyl}-9-methylphenazine-1-carboxamide (76) Anal. (C₃₆ H₃₆ N₆ O₂.H₂ O) C, H, N.

EXAMPLE 77 Preparation of Compound 77 of Table 1 by the Method of Scheme 3

Activation and coupling of phenazine-1-carboxylic acid [Rewcastle, G. W., Denny, W. A., Baguley, B. C., J. Med. Chem., 1987, 30, 843-857] with N-1-{3-[N-methyl-N-(3-aminopropyl)]aminopropyl}-9-methylphenazine-1-carboxamide [see Example 76 for preparation] as above gave N-1-{3-[{3-[(phenazinyl-1-carbonyl)amino]propyl}(methyl)amino]-propyl}-9-methylphenazine-1-carboxamide (77) as a yellow solid, 77%, mp 120° C. (dec.) (CH₂ Cl₂ /n-hexane). ¹ H NMR (CDCl₃) δ 1.96-2.07 (m, 4 H, 2×CH₂ CH₂ CH₂), 2.36 (s, 3 H, NCH₃), 2.65-2.73 (m, 7 H, 2×CH₂ NCH₃ and ArCH₃), 3.68-3.78 (m, 4 H, 2×CH₂ NHCO), 7.47 (dt, J=6.9, 1.1 Hz, 1 H, ArH), 7.57 (ddd, J=8.7, 6.6, 1.2 Hz, 1 H, ArH), 7.63 (dd, J=8.7, 6.8 Hz, 1 H, ArH), 7.71 (ddd, J=8.7, 6.7, 1.5 Hz, 1 H, ArH), 7.87 (dd, J=8.7, 7.2 Hz, 1 H, ArH), 7.90 (dd, J=8.6, 7.1 Hz, 1 H, ArH), 7.94 (d, J=9.2 Hz, 1 H, ArH), 8.00 (d, J=8.6 Hz, 1 H, ArH), 8.08 (d, J=8.5 Hz, 1 H, ArH), 8.21 (dd, J=8.7, 1.5 Hz, 1 H, ArH), 8.31 (dd, J=8.7, 1.5 Hz, 1 H, ArH), 8.89 (dd, J=7.1, 1.5 Hz, 1 H, ArH), 8.92 (dd, J=7.2, 1.5 Hz, 1 H, ArH) and 10.87 (br s, 2 H, 2×NH). Analysis for N-1-{3-[{3-[(phenazinyl-1-carbonyl)amino]propyl}(methyl)amino]-propyl}-9-methylphenazine-1-carboxamide (77) Anal. (C₃₄ H₃₃ N₇ O₂.H₂ O) C, H, N.

EXAMPLE 78 Preparation of Compound 78 of Table 1 by the Method of Scheme 3

Triethylenetetramine was reacted with di-tert-butyldicarbonate according to the method of Blagbrough et al (Pharm. Sciences, 1997, in press; personal communication) to give, after purification by column chromatography (20% MeOH in CH₂ Cl₂ as eluant), N-aminoethyl-N,N'-bis(tert-butoxycarbonyl)-N-[(N-tert-butoxycarbonyl)aminoethyl]ethylenediamine as a pale yellow viscous oil (59%). ¹ H NMR (CDCl₃) ? 1.39-1.50 [m, 29 H, 3×C(CH₃)₃, NH₂ ], 3.00-3.62 (m, 12 H, 6×CH₂), 4.45 (br s, 1 H, NHBOC).

5-Methylacridine-4-carboxylic acid (1.00 g, 4.23 mmol) was reacted with CDI (1.02 g, 6.33 mmol) to form the imidazolide as reported above. The imidazolide was suspended in THF (80 mL) at room temperature, and a solution of the above amine (2.04 g, 4.65 mmol) in THF (20 mL) slowly added. The reaction mixture was then stirred for 18 h. at 20° C. The THF was removed under reduced pressure and the resulting yellow solid was partitioned between CH₂ Cl₂ (200 mL) and 1 M Na₂ CO₃ (200 mL). The CH₂ Cl₂ layer was dried with Na₂ SO₄ and the solvent removed under reduced pressure to give a yellow oil which was purified by column chromatography on alumina (0.5% MeOH in CH₂ Cl₂ as eluant) to give the triBOC analogue of N-1-[2-(N-{2-[N-(2-aminoethyl)]aminoethyl})aminoethyl]-5-methylacridine-4-carboxamide as a yellow foam (1.41 g, 51%). ¹ H NMR (CDCl₃) d 1.46 [m, 30 H, 3×C(CH₃)₃, ArCH₃ ], 3.13-3.65 (m, 12 H, 6×CH₂), 4.43 (br s, 1 H, NHBOC), 7.48-7.55 (m, 1 H, ArH), 7.64-7.74 (m, 2 H, ArH), 7.88-7.94 (m, 1 H, ArH), 8.12-8.19 (m, 1 H, ArH), 8.85-8.90 (m, 1 H, ArH), 8.93-9.00 (m, 1 H, ArH), 12.23 (br s, 1 H, NH).

Trifluoroacetic acid (10 mL) was added to a solution of the above tri-BOC amide (1.00 g, 1.52 mmol) in CH₂ Cl₂ (10 mL). The mixture was stirred at 20° C. for 2 h, at which point the reaction was complete by TLC. All solvents were removed under reduced pressure and the oily residue was partitioned between CHCl₃ (100 mL) and saturated Na₂ CO₃ (20 mL). The aqueous layer was further extracted with additional CHCl₃ (11×100 mL) and all CHCl₃ extracts were combined and dried with Na₂ SO₄. The solvent was removed under reduced pressure to give N-1-[2-(N-{2-[N-(2-aminoethyl)]aminoethyl})aminoethyl]-5-methylacridine-4-carboxamide (533 mg, 98%) as a yellow oil. ¹ H NMR (CDCl₃) d 2.58-2.68 (m, 2 H, CH₂), 2.70-2.76 (m, 4 H, 2×CH₂), 2.82-2.86 (m, 2 H, CH₂), 2.93 (s, 3 H, ArCH₃), 3.03-3.07 (m, 2 H, CH₂), 3.82-3.88 (m, 2 H, CH₂), 7.49-7.55 (m, 1 H, ArH), 7.65-7.75 (m, 2 H, ArH), 7.89-7.94 (m, 1 H, ArH), 8.13-8.18 (m, 1 H, ArH), 8.88 (br d, J=5.3 Hz, 1 H, ArH), 8.98 (td, J=7.1, 1.5 Hz, 1 H, ArH), 12.04 (br s, 1 H, NH).

9-Methylphenazine-1-carboxylic acid (1.00 g, 4.20 mmol) was reacted with CDI (1.02 g, 6.30 mmol) to form the imidazolide which was isolated as above. This imidazolide was suspended in THF (20 mL), the suspension cooled to ) 0° C. (ice/water) then a solution of the above polyamine (529 mg, 1.48 mmol) in THF (20 mL) slowly added. The reaction mixture was stirred for 2 h. at 0° C., then 18 h. at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between CH₂ Cl₂ (100 mL) and 1 M Na₂ CO₃ (100 mL). The CH₂ Cl₂ layer was dried with Na₂ SO₄ and the solvent removed under reduced pressure to give a yellow solid (553 mg, 61%) which was purified by column chromatography on alumina (2% MeOH in CH₂ Cl₂ as eluant) to give N-1-(2-{[2-({2-[(5-methylacridinyl-4-carbonyl)amino]ethyl}amino)ethyl]amino}-ethyl)-9-methylphenazine-1-carboxamide (78) as a yellow solid. ¹ H NMR (CDCl₃) d 2.77 (s, 3 H, ArCH₃), 2.79 (s, 3 H, ArCH₃), 2.82-2.88 (m, 4 H, 2×CH₂), 2.97 (t, J=6.0 Hz, 2 H, CH₂), 3.02 (t, J=6.0 Hz, 2 H, CH₂), 3.70 (q, J=5.9 Hz, 2 H, CH₂), 3.79 (q, J=6.0 Hz, 2 H, CH₂), 7.31 (dd, J=8.4, 6.8 Hz, 1 H, ArH), 7.51-7.70 (m, 5 H ArH), 7.87 (dd, J=8.5, 7.1 Hz, 1 H, ArH), 7.91-7.96 (m, 2 H, ArH), 8.26 (dd, J=8.7, 1.5 Hz, 1 H, ArH), 8.57 [s, 1 H, H-9 (acridine)], 8.85-8.91 (m, 2 H, ArH), 10.83 [br t, J=5.1 Hz, 1 H, NH (phenazine)], 11.83 [br t, J=5.4 Hz, 1 H, NH (acridine)].

EXAMPLE 79 Preparation of Compound 79 of Table 1 by the Method of Scheme 3

Ethylenediamine was alkylated with an excess of chloroacetonitrile according to the method of Overman and Burk [Bradshaw et al, Tetrahedron, 1992, 48, 4475], and the product was purified by filtration through a plug of flash silica (1% MEOH in CH₂ Cl₂ as eluant) to give give N,N'-bis(cyanomethyl)ethylenediamine as a yellow oil which solidified upon cooling *88%), mp 41-42° C. ¹ H NMR (CDCl₃) d 1.58 (s, 2 H, 2×NH), 2.90 (s, 4 H, 2×CH₂), 3.63 (s, 4 H, 2×CH₂).

The above diamine (3.00 g, 21.7 mmol) in a mixture of THF (90 mL), water (10 mL) and triethylamine (10 mL) was treated with di-tert-butyldicarbonate (19.0 g, 87.0 mmol). All solvents were removed under reduced pressure and the resulting residue was partitioned between water (100 mL) and EtOAc (2×100 mL). The combined EtOAc layers were dried (Na₂ SO₄), the solvent removed, and the resulting pale brown solid purified by flash chromatography on silica (50% EtOAc/PE as eluant) to give N,N'-bis(tert-butoxycarbonyl)-N,N'-bis(cyanomethyl)ethylenediamine as a white solid (6.59 g, 90%), mp 112-113° C. (EtOAc/peteroleum ether). ¹ H NMR (CDCl₃) d 1.50 [s, 18 H, 2×C(CH₃)₃ ], 3.52 (s, 4 H, 2×CH₂), 4.13 (br s, 4 H, 2×CH₂).

Hydrogenation of the above with W-7 Raney nickel, according to a reported procedure [Ravikumar, Syn. Commun., 1994, 24, 1767] gave N,N'-bis(aminoethyl)-N,N'-bis(tert-butoxy carbonyl)ethylenediamine as a white solid (100%), mp 81-82° C. ¹ H NMR (CDCl₃) d 1.46 [s, 18 H, 2×C(CH₃)₃ ], 1.57 (br s, 4 H, 2×NH₂), 2.83 (br s, 4 H, 2×CH₂), 3.30 (br m, 8 H, 4×CH₂).

The above diamine was reacted with ethyl trifluoroacetate according to the method of Blagbrough et al (Pharm. Sciences, 1997, in press; personal communication) to give N-aminoethyl-N,N'-bis(tert-butoxycarbonyl)-N'-[(N-trifluoroacetamido)aminoethyl]-ethylenediamine as a clear oil (39%). ¹ H NMR (CDCl₃) d 1.46 [s, 18 H, 2×C(CH₃)₃ ], 1.95 (br s, 2 H, NH₂), 2.84-2.96 (m, 2 H, CH₂), 3.20-3.48 (m, 10 H, 5×CH₂), 7.99, 8.21, 8.51 (all br s, total 1 H, NH).

Phenazine-1-carboxylic acid (212 mg, 0.95 mmol) was reacted with CDI (230 mg, 1.42 mmol) to form the imidazolide, which was isolated as above. The imidazolide was then suspended in THF (10 mL) and a THF (10 mL) solution of the above monotrifluoroacetamide (416 mg, 0.95 mmol) slowly added to the solution. This mixture was allowed to stir at room temperature for 18 h., whereupon the solvent was removed under reduced pressure and the residue partitioned between CH₂ Cl₂ (100 mL) and 1 M Na₂ CO₃ (50 mL). The CH₂ Cl₂ layer was then dried with Na₂ SO₄ and the solvent removed under reduced pressure to give a residue that was purified by chromatography on alumina (0.5%. MeOH in CH₂ Cl₂ as eluant) to give N-1-{2-[N'-tert-butoxycarbonyl-N'-(2-{N-tert-butoxycarbonyl-N-[2-(N-trifluoroacetamido)aminoethyl]aminoethyl)]-aminoethyl}phenazine-1-carboxamide as a yellow oil (558 mg, 91%). ¹ H NMR (CDCl₃) d 1.39 [br s, 9 H, C(CH₃)_(3]) 1.43 [br s, 9 H, C(CH₃)₃ ], 3.31-3.68 (m, 10 H, 5×CH₂), 3.82-3.89 (m, 2 H, CH₂), 7.90-8.44 [m, 7 H, 6×ArH, NHC(O)CF₃ ], 8.99 (br s, 1 H, ArH), 11.13 (br s, 1 H, CONH).

A solution of the above trifluoroacetamide (548 mg, 0.85 mmol) in a mixture of MeOH (30 mL) and H₂ O (20 mL) was treated with K₂ CO₃ (584 mg, 4.23 mmol). This reaction was stirred and heated at reflux for 2 h., followed by room temperature for 18 h. Clean conversion of the trifluoroacetamide to the free amine was observed by TLC. The MeOH was removed under reduced pressure, then saturated Na₂ CO₃ (20 mL) added to the residue and this aqueous portion extracted with CHCl₃ (2×50 mL). The combined CHCl₃ portions were dried with Na₂ SO₄, then the solvent removed under reduced pressure to afford N-1-[2-(N'-tert-butoxycarbonyl-N'-{2-[N-(aminoethyl)-N-tert-butoxycarbonyl]-aminoethyl})aminoethyl]phenazine-1-carboxamide (470 mg, 100%) ¹ H NMR (CDCl₃) d 1.38 [br s, 9 H, C(CH₃)₃ ], 1.43 [br s, 9 H, C(CH₃)₃ ], 2.78 (t, J=6.5 Hz, 2 H, NH₂), 3.18-3.70 (m, 10 H, 5×CH₂), 3.81-3.90 (m, 2 H, CH₂), 7.89-8.00 (m, 3 H, ArH), 8.21-8.43 (m, 3 H, ArH), 9.00 (br s, 1 H, ArH), 11.08 (br s, 1 H, CONH).

Acridine-4-carboxylic acid (192 mg, 0.86 mmol) was reacted with CDI (210 mg, 1.29 mmol) to form the imidazolide which was isolated as above. The resulting imidazolide was then suspended in THF (20 mL) and a THF (10 mL) solution of the above amine (470 mg, 0.86 mmol) added slowly to the stirred solution. This mixture was allowed to stir at room temperature for 18 h., whereupon the solvent was removed under reduce pressure and the residue partitioned between CH₂ Cl₂ (100 mL) and 1 M Na₂ CO₃ (50 mL). The CH₂ Cl₂ layer was dried with Na₂ SO₄ and the solvent removed under reduced pressure to give a residue which was purified by column chromatography on alumina (0.5% MeOH in CH₂ Cl₂ as eluant) to give N-1-(2-{[2-({2-[(acridinyl-4-carbonyl)amino]ethyl}N-tert-butoxycarbonyl amino)ethyl]N'-tert-butoxycarbonyl amino}ethyl)phenazine-1-carboxamide as a yellow oil (568 mg, 89%). ¹ H NMR (CDCl₃) d 1.42 [br s, 9 H, C(CH₃)₃ ], 1.46 [br s, 9 H, C(CH₃)₃ ], 3.37-3.69 (m, 10 H, 5×CH₂), 3.81-3.89 (m, 2 H, CH₂), 7.09-7.15 (m, 1 H, ArH), 7.25 (t, J=7.4 Hz, 1 H, ArH), 7.36 (d, J=8.3 Hz, 1 H, ArH), 7.64 (t, J=7.2 Hz, 1 H, ArH), 7.83-7.97 (m, 4 H, ArH), 8.11-8.27 (m, 3 H, ArH), 8.31-8.45 (m, 2 H, ArH), 8.53-8.61 (br s, 1 H, ArH), 8.89-8.99 (br s, 1 H, ArH), 11.10 [s, 1 H, CONH (phenazine)], 12.52 [s, 1 H, CONH (acridine)].

Gaseous HCl was bubbled through MeOH until the solution was strongly acidic to pH paper. The above protected amine was dissolved in this solution (20 mL) and stirred at room temperature for 18 h. The MeOH was removed under reduced pressure and the residue dissolved in saturated Na₂ CO₃ (50 mL) which was then extracted with CHCl₃ (13×50 mL). The combined CHCl₃ extacts were dried with Na₂ SO₄, then the solvent removed under reduced pressure to give N-1-(2-{[2-({2-[(acridinyl-4-carbonyl)amino]ethyl}amino)ethyl]amino}ethyl)phenazine-1-carboxamide (79) as a yellow solid (159 mg, 96%) mp 173-176° C. (CH₂ Cl₂ /MeOH). ¹ H NMR (CDCl₃) d 2.83-2.96 (m, 6 H, 3×CH₂), 3.07 (t, J=5.9 Hz, 2 H, CH₂), 3.46 (q, J=5.3 Hz, 2 H, CH₂), 3.80 (q, J=5.8 Hz, 2 H, CH₂), 7.01 (t, J=7.8 Hz, 1 H, ArH), 7.25 (ddd, J=8.1, 7.2, 0.9 Hz, 1 H, ArH), 7.32 (d, J=8.2 Hz, 1 H, ArH), 7.55 (br s, 1 H, ArH), 7.65 (ddd, J=8.3, 7.0, 1.5 Hz, 1 H, ArH), 7.79-7.90 (m, 4 H, ArH), 8.12-8.16 (m, 2 H, ArH), 8.26 (dd, J=8.7, 1.5 Hz, 1 H, ArH), 8.39 (dd, J=8.1, 1.3 Hz, 1 H, ArH), 8.43 (dd, J=8.1, 1.4 Hz, 1 H, ArH), 8.89 (dd, J=7.1, 1.5 Hz, 1 H, ArH), 11.11 [s, 1 H, CONH (phenazine)], 12.20 [s, 1 H, CONH (acridine)].

EXAMPLE 80 Biological Testing of Compounds of the Invention. In vitro Testing

The in vitro cytotoxicity of the compounds of the present invention was evaluated by studies on murine P388 leukemia, the late-passage murine Lewis lung carcinoma line LLTC, and a wild-type human leukemia line (Jurkat; JL_(C)). Cells were grown as reported by Finlay et al. in Oncol. Res. 1994, 6, 33-37 and in Eur. J. Cancer 1996, 32A, 708-714, and growth inhibition assays were performed by culturing cells at 4×10³ (P388), 10³ (LLTC) and 3.75×10³ (Jurkat lines) per well in microculture plates (150 μL per well) for 3 (P388) or 4 days in the presence of drug. Cell growth was determined by [³ H]TdR uptake (P388) as described by Marshall et al. in, J. Natl. Cancer Inst. 1992, 84, 340-345 or the sulforhodamine assay as described by Skehan et al. in, J. Natl. Cancer Inst. 1990, 82, 1107-1112. Independent assays were performed in duplicate, and coefficients of variation were 12% (P388), 12% (LLTC) and 6.3% (JL_(C)).

                  TABLE II                                                         ______________________________________                                         Biological activities of selected compounds of                                 formula (I) listed in Table I.                                                 IC.sub.50 values (nM)                                                          No      P388           LLTC    JL.sub.c                                        ______________________________________                                         6                      <6      11                                              7       170                                                                    8                      738     1540                                            9                      1086    2543                                            10      620            167     345                                             11                     32      87                                              12                     8       33                                              13      10             7       28                                              14      15             39      114                                             15      76             17      58                                              16      27             20      52                                              17      59             13      66                                              18      49             17      69                                              19                     165     380                                             20                     322     223                                             21      370            73      275                                             22      1370           795     1640                                            23      1500           2079    2079                                            24      1630           1620    1300                                            26                     20      147                                             27      138            36      99                                              28      190            <24     137                                             29      220            36      226                                             31      1293           41      250                                             33      56             81      110                                             34      320            209     473                                             35      260            81      93                                              36      140            18      102                                             36      520            119     137                                             41                     151     209                                             42                     74      300                                             43      600            64      195                                             44                     83      274                                             45                     142     175                                             46                     24      30                                              47                     2.2     4.8                                             51      500            1310    1250                                            52                     120     172                                             53                     8.8     14                                              54      44             8.5     16                                              55      2130           671     1550                                            56      972            183     760                                             57      35             3.2     11                                              58      *              1.1     3.8                                             59      41             8.8     20.3                                            60      *              5.0     13                                              61      435            48      208                                             62      204            12      74                                              63      12,300         8370    2370                                            64      94             43.5    42.3                                            65      26             5.3     21.3                                            66      33             5.2     9.8                                             67      *              17      85                                              68      *              33.6    1.2                                             69      *              3.9     0.55                                            70      *              112     8.7                                             71      24             7.7     0.6                                             72      630            >50     6.9                                             73      <6.2           1.2     0.24                                            74      39             10.5    0.6                                             75      *              78      272                                             76      *              1.8     8.8                                             77      *              19      31                                              ______________________________________                                    

In vivo testing

Selected compounds of general formula (I) also showed activity in vivo against sub-cutaneous colon 38 tumors in mice. These data are illustrated in the accompanying FIG. 1 for compounds 13 (at 60 mg/kg) and 17 (at 90 mg/kg). In this assay, colon 38 tumors were grown subcutaneously from 1 mm³ fragments implanted sc in one flank of anaesthetised mice (pentobarbitone 90 mg/kg). Treatment began once they had reached a diameter of approximately 4 mm (normally after 7 days). Mice were divided into groups of 5 for control and drug treated groups, with average tumor volumes similar for each of the groups. Drugs were dissolved either in distilled water or 15% aqueous ethanol, and injected in a volume of 0.01 ml per gram of body weight in a split dose of two equal injections administered one hour apart. Mice were monitored closely, and weighed after 7 days to check for drug-induced weight loss. Mice were killed when the average tumor diameter exceeds 20 mm. Tumor diameters were measured with callipers three times weekly, and tumor volumes were calculated as 0.52`a² `b, where a and b are the minor and major tumor axes. Data were plotted on a semilogarithmic plot (mean tumor volume versus time after treatment), and the time taken for tumors to reach a mean volume four-fold higher than their pre-treatment volume was calculated. From this, tumor growth delays relative to control mice were calculated. 

What is claimed is:
 1. A compound which is a bis(acridinecarboxamide) or bis(phenazinecarboxamide) of formula (I): ##STR12## wherein each X, which may be the same or different in a given molecule, is --CH═ or --N═, each of R₁ to R₄ which may be the same or different, is H, C₁ -C₄ alkyl, OH, SH, NH₂, C₁ -C₄ alkoxy, phenyl, phenyloxy, CF₃, NO₂, halogen, NHR, N(R)₂, SR or SO₂ R wherein R is C₁ -C₄ alkyl, or R₁ and R₂ together form a methylenedioxy group; each of R₅ and R₆, which may the same or different, is H or C₁ -C₄ alkyl; Z is (CH₂)_(n), (CH₂)_(n) O(CH₂)_(n), (CH₂)_(n) N(R₇)(CH₂)_(n), (CH₂)_(n) N(R₇)(CH₂)_(m) N(R₇)(CH₂)_(n) or ##STR13## wherein R₇ is H or C₁ -C₄ alkyl and n and m, which may be the same or different, are each an integer of 1 to 4; or a pharmaceutically acceptable acid addition salt or N-oxide thereof; with the exception of compounds wherein each X is N, each of R₁ to R₆ is H, the carboxamide moiety is attached to position 1 of each phenazine ring and Z is (CH₂)₂ NH(CH₂)₂, (CH₂)₃ NH(CH₂)₃, ##STR14## (CH₂)₂ NH(CH)₂ NH(CH₂)₂ or (CH₂)₃ NH(CH₂)₂ NH(CH₂)₃.
 2. A compound which is a bis(acridinecarboxamide) or bis(phenazinecarboxamide) of formula (I): ##STR15## wherein each X, which may be the same or different in a given molecule, is --CH═ or --N═, each of R₁ to R₄ which may be the same or different, is H, C₁ -C₄ alkyl, OH, SH, NH₂, C₁ -C₄ alkoxy, phenoxy, CF₃, NO₂, halogen, NHR, N(R)₂, SR, or SO₂ R wherein R is C₁ -C₄ alkyl, or R₁ and R₂ together form a methylenedioxy group; each of R₅ and R₆, which may be the same or different, is H or C₁ -C₄ alkyl; Z is (CH₂)_(n), (CH₂)_(n) O(CH₂)_(n), (CH₂)_(n) N(R₇)(CH₂)_(n), (CH₂)_(n) N(R₇)(CH₂)_(m) N(R₇)(CH₂)_(n) or ##STR16## wherein R₇ is H or C₁ -C₄ alkyl and n and m, which may be the same or different, are each an integer of 1 to 4; or a pharmaceutically acceptable acid addition salt or N-oxide thereof; with the exception of compounds wherein each X is N, each of R₁ to R₆ is H, the carboxamide moiety is attached to position 1 of each phenazine ring and Z is (CH₂)₂ NH(CH₂)₂, (CH₂)₃ NH(CH₂)₃, ##STR17## (CH₂)₂ NH(CH₂)₂ NH(CH₂)₂ or (CH₂)₃ NH(CH₂)₂ NH(CH₂)₃.
 3. A compound according to claim 1 or 2 which is a bis(acridine carboxamide) of the formula (Ia): ##STR18## wherein each of R₁ and R₃, which are the same or different, is C₁ -C₄ alkoxy, C₁ -C₄ alkyl or halogen, each of R₂ and R₄, which are the same or different, is hydrogen, C₁ -C₄ alkoxy, C₁ -C₄ alkyl or halogen, and each of R₅ and R₆ is H; or a pharmaceutically acceptable salt or N-oxide thereof.
 4. A compound according to claim 1 which is a bis(phenazinecarboxamide) of formula (Ib): ##STR19## wherein each of R₁ and R₃, which are the same or different, is C₁ -C₄ alkoxy, C₁ -C₄ alkyl or halogen, each of R₂ and R₄, which are the same or different, is hydrogen, C₁ -C₄ alkoxy, C₁ -C₄ alkyl or halogen, and each of R₅ and R₆ is H; or a pharmaceutically acceptable salt or N-oxide thereof.
 5. A process for producing a compound as defined in claim 1 or 2, which process comprises reacting two moles of an acridinecarboxylic acid or 9-azaacridine carboxylic acid of formula (II): ##STR20## wherein R₁, R₂ and X are as defined in claim 1 and A is OH, Cl or N-imidazolyl, with one mole of a bis(amine) of formula (III):

    NHR.sub.5 --Z--NHR.sub.6                                   (III)

wherein R₅, R₆, and Z are as defined in claim 1; and, if desired, converting the resulting compound into a pharmaceutically acceptable acid addition salt or N-oxide thereof.
 6. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound as defined in claim 1 or
 2. 7. A method of treating a human or animal patient harboring a tumor, which method comprises administering thereto a therapeutically effective amount of a compound as defined in claim
 1. 8. A method according to claim 1 wherein the tumor is selected from the group consisting of lung and colon tumors, melanoma and central nervous system (CNS) tumors. 